Physiol Rev 91: 1219 –1243, 2011
doi:10.1152/physrev.00001.2011
THE UNFOLDED PROTEIN RESPONSE:
INTEGRATING STRESS SIGNALS THROUGH THE
STRESS SENSOR IRE1␣
Claudio Hetz, Fabio Martinon, Diego Rodriguez, and Laurie H. Glimcher
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Department of Medicine,
Harvard Medical School, and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of
Technology and Harvard University, Boston, Massachusetts; Center for Molecular Studies of the Cell, Institute
of Biomedical Sciences, and Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile,
Santiago, Chile; and Department of Biochemistry, University of Lausanne and Center of Infection and Immunity
Lausanne, Epalinges, Switzerland
L
1219
1221
1223
1224
1228
1229
1231
1233
1236
1237
After passing the ER quality control process, properly
folded proteins traffic in vesicular membranes to various
organelles, the cell surface, or the extracellular space. After
translocation to the ER, nascent proteins fold assisted by a
complex network of foldases, chaperones, and cofactors
(34, 72, 146). Some of the better described folding catalysts
are immunoglobulin binding protein BiP (also known as
glucose-regulated protein 78, Grp78) and Grp94, the protein disulfide isomerases Erp57 and PDI, calnexin, and calreticulin, among many other enzymes (40, 126, 137).
The endoplasmic reticulum (ER) is an essential subcellular
compartment responsible for the synthesis and folding of
proteins that traffic through the secretory pathway. This
organelle is the site for executing and regulating many posttranslational modifications that ensure protein function
(34, 46). The ER serves as the major intracellular calcium
store, and also plays a crucial role in the biosynthesis of
cholesterol, steroids, and other lipids, regulating second
messenger signaling.
Although large families of distinct chaperones and foldases
are expressed in the ER lumen, little is known about how
protein folding networks are arranged at the ER, and what
controls the substrate specificity for these protein folding
pathways. The best described folding/quality control network at the ER is the calnexin and calreticulin cycle. In this
pathway, ERp57 associates with calnexin and/or calreticulin to assist the folding and quality control of a subset of
glycoproteins. PDI and ERp57 are part of a group of oxidoreductases responsible for catalyzing the formation, reduction, and isomerization of disulfide bonds (158). In theory, most glycol-polypeptides are released from calnexin/
calreticulin/ERp57 in a folded state. After passing this
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
INTRODUCTION
UPR SIGNALING
CHRONIC ER STRESS AND...
REGULATION OF IRE1␣ ACTIVATION...
XBP1s BIOLOGY AND REGULATION
ADDITIONAL IRE1␣ DOWNSTREAM...
THE UPROSOME: MODULATION OF...
ROLE OF THE IRE1/XBP1 PATHWAY...
ACTIVATION OF THE IRE1/XBP1...
DISCUSSION
I. INTRODUCTION
A. The Endoplasmic Reticulum
1219
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Hetz C, Martinon F, Rodriguez D, Glimcher LH. The Unfolded Protein Response:
Integrating Stress Signals Through the Stress Sensor IRE1␣. Physiol Rev 91: 1219 –
1243, 2011; doi:10.1152/physrev.00001.2011.—Stress induced by accumulation
of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory
cells and is observed in many tissues in human diseases including cancer, diabetes,
obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the
unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER
homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1␣), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the
transcription factor X-box binding protein-1 (XBP1). IRE1␣ signaling is a highly regulated process,
controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory
mechanisms underlying IRE1␣ function and discuss the emerging role of the UPR in adaptation to
protein folding stress in specialized secretory cells and in pathological conditions associated with
alterations in ER homeostasis.
THE UNFOLDED PROTEIN RESPONSE
quality control step, proteins undergo glucose trimming
(49), to undergo transport to other compartments. A percentage of the newly synthesized glycoproteins do not reach
a final folded state and enter into an additional folding cycle
likely to consist of a disulfide reshuffling. Terminally unfolded/misfolded proteins are delivered for proteasome-mediated degradation by the ER-associated degradation
(ERAD) pathway (FIG. 1) (11, 181). Although the calnexin
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 1. The calnexin cycle. The folding of glycosylated proteins at the ER is regulated by the calnexin cycle.
After nascent chains enter the ER, lumen proteins are glycosylated by the oligosaccharyltransferase. The two
terminal glucose residues are rapidly trimmed. Mono-glucosylated N-glycans mediate initial association of
folding polypeptides with the ER lectin chaperones calnexin (CNX) and/or calreticulin (CRT) and exposure to
ERp57 through a protein complex. It is likely that most glycopolypeptides are released from calnexin/
calreticulin/ERp57 in a native, transport competent state. Glycopolypeptides released from calnexin displaying
major folding defects are attracted by BiP and are dislocated across the ER membrane for ubiquitination (U)
and proteasome-mediated degradation through a pathway known as ERAD.
1220
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
HETZ ET AL.
cycle is proposed to be essential for the folding of glycoproteins, different studies using genetic manipulation suggest
that this pathway may be relevant for the folding and quality control of only a small subset of glycoproteins (158,
188). In general, most of the folding components and networks expressed at the ER remain poorly characterized.
B. Protein Folding Stress at the ER
Physiological fluctuations in the demand for protein synthesis and secretion as part of the development and differentiation of specialized secretory cells lead to the occurrence of
ER stress. Physiological levels of ER stress engage the UPR
to maintain protein homeostasis, and directly contribute to
the development and maintenance of a differentiated and
functional state of specialized secretory cells such as pancreatic beta cells, B cell lymphocytes, and salivary gland
cells (reviewed in Ref. 109). ER stress is also triggered by
many conditions that alter protein homeostasis networks.
These perturbations include altered protein maturation,
modification of chaperone function, expression of diseaserelated mutant proteins, decreased ER calcium content, and
redox alterations among others (9, 162). There is growing
biomedical interest in investigating the regulatory mechanisms underlying UPR signaling and the development of
strategies to target this pathway, since there is substantial
evidence for the involvement of chronic ER stress in many
diseases, including neurodegeneration (54, 127), diverse
forms of cancer (83, 122), diabetes (101), and proinflammatory conditions (176). Here, we summarize current
thinking on this topic and provide our view of the impact of
ER stress in physiological and pathological settings.
II. UPR SIGNALING
A. UPR Stress Sensors
The major impact of the UPR is the maintenance of protein
homeostasis in the context of high unfolded protein load.
In yeast, the UPR is controlled by only one signaling pathway,
mediated by a type I transmembrane ER protein known as
IRE1p (inositol-requiring transmembrane kinase/endonuclease) (22, 123, 166). In higher eukaryotes, the UPR is mediated by at least three classes of stress sensors including IRE1␣
and IRE1␤, PERK (PKR-like ER kinase), and ATF6␣ and
ATF6␤ (activating transcription factor 6) (FIG. 3). These three
UPR branches control the expression of specific transcription
factors and signaling events that modulate a variety of UPR
downstream responses, orchestrating adaptation to ER stress.
In this review we address in detail the current proposed mechanisms underlying UPR signaling, stress sensing, and downstream effectors as well as their relevance to physiology and
disease. We also speculate about possible mechanisms that
explain the transition from adaptive UPR responses to apoptosis under chronic ER stress. We will provide a brief general
overview of UPR signaling and then focus primarily on the
IRE1␣ branch of the UPR, probably the best characterized of
the three arms of the ER stress pathway.
B. PERK and ATF4 Signaling
PERK is a type I ER transmembrane protein kinase that
upon activation inhibits general protein translation into the
ER through the inactivation of the initiation factor eIF2␣ by
serine 51 phosphorylation. This phosphorylation inhibits
the guanine nucleotide exchange factor eIF2B, a complex
that recycles eIF2␣ to its active GTP-bound form. This inhibitory effect of translation helps alleviate ER stress by
decreasing the overload of misfolded proteins (162). In addition, eIF2␣ phosphorylation is reversible, but the identity
of the phosphatases involved in this process is not clear.
However, two components of this negative regulation pathway include growth arrest and DNA-damage inducible protein-34 (GADD34) and constitutive repressor of eIF2␣
phosphorylation (CReP) (162).
In addition, eIF2␣ phosphorylation preferentially increases
the translation of selective mRNAs that contain inhibitory
upstream open reading frames (uORFs) within their 5= untranslated region (UTR) that prevent translation in unstressed cells. The most studied of these genes is activating
transcription factor 4 (ATF4) (162). ATF4 is a transcription factor that upregulates a subset of UPR genes that
function preferentially in amino acid import, glutathione
biosynthesis, and resistance to oxidative stress (43, 110,
167, 208) (FIG. 2). Attempts to define the universe of
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1221
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
The extremely high concentration of proteins within the ER
(100 mg/ml) renders this organelle’s environment very susceptible to protein aggregation (126, 170). Different physiological and pathological perturbations interfere with protein folding processes in the ER lumen, leading to accumulation of unfolded or misfolded proteins, a cellular condition
termed “ER stress.” Protein folding stress triggers the activation of an adaptive reaction to cope with ER stress termed
the unfolded protein response (UPR). The UPR is a complex
signal transduction pathway that conveys information
about protein folding status in the ER lumen to increase
protein folding capacity and decrease unfolded protein
load. If these mechanisms of adaptation and survival are
insufficient to recover ER homeostasis, cells undergo cell
death by apoptosis.
To accomplish this, the UPR reprograms the transcriptome
modulating the expression of a vast number of secretory
pathway-related genes. Gene expression profiling studies
indicate that the UPR regulates a variety of genes involved
in specific secretory pathway-related processes including
protein entry into the ER, folding, glycosylation, redox metabolism, protein quality control, protein degradation, lipid
biogenesis, and vesicular trafficking (FIG. 2).
THE UNFOLDED PROTEIN RESPONSE
PERK-dependent UPR target genes in mammalian cells
revealed that nearly half of the PERK-dependent targets
are ATF4 independent (15, 43), suggesting the existence
of other PERK downstream effectors. It is not clear if
other PERK substrates exist, but PERK may also phosphorylate nuclear factor (erythroid-derived 2)-like 2
(NRf2) (26, 27). Nrf2 is a transcription factor that controls the regulation of oxidative stress responses (27, 47).
Although controversial (155), it has been suggested that
PERK may also control the expression of NF-␬B in an
ATF4-independent manner. In addition to its response to
ER stress, eIF2␣ is also phosphorylated by other kinases
linked to amino acid starvation and double-stranded
RNA accumulation, indicating that the cellular responses
controlled by this UPR signaling branch are not solely
restricted to protein folding stress.
1222
C. ATF6 Signaling
Another UPR pathway is mediated by ATF6␣ and ATF6␤,
type II ER transmembrane proteins which encode bZIP
transcription factor domains in the cytosolic region of the
protein (45, 196). ATF6 is synthesized as an inactive precursor, retained at the ER by a transmembrane spanning
segment. Under ER stress conditions, ATF6 translocates to
the Golgi where it is processed, first by site 1 protease and
then in an intramembrane region by site 2 protease. This
proteolytic processing releases its cytoplasmic domain,
ATF6f (a fragment of ATF6), which operates as a transcriptional activator that upregulates many UPR genes related
to ERAD and protein folding, among other processes
(45, 92, 192) (FIG. 2). Interestingly, there are many other
putative ATF6 homologs identified, which are modulated
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 2. The unfolded protein response (UPR). Accumulation of abnormally folded proteins at the ER
engages an adaptive stress response known as the UPR. There are three major ER stress sensors, IRE1␣,
PERK, and ATF6, which transduce information about the folding status of the ER to the cytosol and nucleus to
restore folding capacity. Activation of IRE1␣ controls selective mRNA decay and also leads to the processing
of the mRNA encoding XBP1, a transcription factor that upregulates many essential UPR genes involved in
folding, organelle biogenesis, ERAD, autophagy, and protein quality control. Active IRE1␣ also regulates stress
responses mediated by JNK, ERK, and NF␬B. Activation of PERK decreases the general protein synthesis rate
through phosphorylation of the initiation factor eIF2␣ and also phosphorylates Nrf2. eIF2␣ phosphorylation, in
contrast, increases the specific translation of the ATF4 mRNA, which encodes a transcription factor that
induces the expression of genes involved in amino acid metabolism, autophagy, antioxidant responses, and
apoptosis. ATF6 is a type II ER transmembrane protein encoding a bZIP transcriptional factor in its cytosolic
domain that is localized at the ER in unstressed cells. Upon ER stress induction, ATF6 is processed at the Golgi
apparatus, releasing its cytosolic domain, which then translocates to the nucleus where it increases the
expression of some ER chaperones, ERAD-related genes, and proteins involved in ER/GA expansion.
HETZ ET AL.
by ER stress in specific tissues, including CREBH (160,
199), OASIS (79, 124), CREB4 (171), LUMAN/CREB3
(96), and BBF2H7 (80, 159). All of these ATF6-related
bZip factors are processed at the Golgi as described for
ATF6, but their function, if any, in the UPR is poorly
characterized.
D. IRE1␣ Signaling
Although IRE1␣ initiates the most conserved signaling
pathway of the UPR, little is known about its biochemical
regulation. IRE1␣ is a Ser/Thr protein kinase and endoribonuclease that catalyzes the unconventional processing
of the mRNA encoding the transcriptional factor X-Box
binding protein-1 (XBP1) (18, 92, 195) (FIG. 4A). A 26nucleotide intron of xbp1 mRNA is spliced out by IRE1␣
in mammalian cells, leading to a shift in the codon reading frame of the mRNA that generates a new COOHterminal end that contains a potent transactivation domain (FIG. 4A).
The spliced version of XBP1 (termed XBP1s) controls the
upregulation of a general pool of UPR-related genes involved in different processes including protein folding, protein entry to the ER, and ERAD (91, 164). In addition,
XBP1s indirectly regulates the biogenesis of the ER and
Golgi by enhancing the activity of enzymes related to phospholipid biosynthesis (164, 168, 169). The universe of
XBP1s target genes differs in different tissues or under different conditions of ER stress (1), possibly reflecting the fact
that XBP1 can interact and heterodimerize with other transcription factors (see below).
III. CHRONIC ER STRESS AND THE
UNFOLDED PROTEIN RESPONSE:
THE APOPTOSIS PHASE
Under chronic ER stress, cells undergo cell death by apoptosis (35, 153), where several pro-apoptotic members of the
BCL-2 family of proteins are essential for the elimination of
irreversibly damaged cells (FIG. 5). The BCL-2 family of
proteins is formed of pro- and anti-apoptotic members
classified by the presence of up to four BCL-2 homology
(BH) domains (28). The initiation of intrinsic apoptosis is
mediated by the activation of pro-apoptotic “multidomain” members (i.e., BAX and BAK) at the mitochondria, leading to the release of cytochrome c and activation of the caspase cascade (198). Upstream regulators of
BAX and BAK contain only the BH3 domain termed
“BH3-only proteins” (17, 150, 198). Initial studies identified the transcriptional upregulation of two BH3-only
proteins, PUMA and NOXA, in cells undergoing ER
stress, which operate as relevant pro-apoptotic inducers
(FIG. 5) (95, 147). Furthermore, upregulation of BIM at
the transcriptional and posttranslational level also contributes to apoptosis by irreversible ER stress (144).
IRE1␣ also activates the ASK1 and JNK pathway, which
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1223
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 3. ER stress sensors. Inositol requiring kinase 1 (IRE1␣), protein kinase-like endoplasmic reticulum
kinase (PERK), and activating transcription factor 6 (ATF6). bZIP, basic leucine zipper; GLS, Golgi localization
sequences; TAD, transcriptional activation domain; TM, transmembrane domain.
THE UNFOLDED PROTEIN RESPONSE
is a relevant factor for the induction of apoptosis by ER
stress (69, 74, 116).
Sustained PERK has a bifunctional role in adaptation to
ER stress and apoptosis (98). Expression of ATF4 and
possibly ATF6 controls the upregulation CCAAT/enhancer binding protein (C/EBP) homologous protein
(CHOP), also termed growth arrest and DNA damageinducible gene (GADD153). CHOP has a pro-apoptotic
activity with an unclear mechanism of action. CHOP
may trigger cell death by downregulation of BCL-2 (117)
and the transcriptional upregulation of BIM (144),
PUMA (36), and GADD34 (110, 144) (FIG. 5) . Many
other regulators of apoptosis in the setting of ER stress
have been described and are reviewed elsewhere (165).
We and others have speculated that the transition be-
1224
tween adaptive UPR programs and the elimination of
irreversibly damaged cells by apoptosis depend in part on
the duration of ER stress stimulation (191).
IV. REGULATION OF IRE1␣ ACTIVATION
AND SIGNALING
Recent studies have uncovered many important aspects of
how protein misfolding is detected by UPR stress sensors. In
this section we discuss the key findings that have revealed
the biochemical basis of IRE␣ activation by ER stress, the
dynamics of this process in terms of assembling IRE1 oligomers, and its inactivation under prolonged ER stress conditions. In addition, we summarize recent interesting models proposed for the targeting of XBP1/HAC1 to IRE1 in the
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 4. Regulation of XBP1s expression and activity. A: schematic representation of the unspliced and
spliced forms of XBP1 (XBP1u and XBP1s, respectively). Numbers indicate amino acid positions. ORF1 and
ORF2 for the COOH-terminal domain as well as the basic and leucine zipper (ZIP) domains are indicated. The
hydrophobic region (HR) shown to target XBP1u to membranes is also highlighted. The translational pausing
(TP) domain is also indicated. B: XBP1s is regulated through posttranslational modifications like acetylation
that enhances its activity, and sumoylation that represses it. The unspliced XBP1 mRNA is translated in
mammals but is rapidly degraded. A hydrophobic region (HR) on the nascent peptide targets the translated
XBP1 mRNA to the ER membrane, enhancing its processing by IRE1␣. In addition, under prolonged ER stress,
XBP1u accumulates and may dimerize with XBP1s to target it for proteasome-mediated degradation.
HETZ ET AL.
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 5. ER stress-mediated apoptosis. The BCL-2 protein family plays an essential role in the control of
apoptosis under prolonged or chronic ER stress. Activation of the pro-apoptotic BCL-2 family members BAX
and BAK at the mitochondria is a key step in the induction of apoptosis, leading to the release of cytochrome
c and activation of downstream caspases. Upstream regulators of BAX and BAK are the BH3-only proteins,
another subset of pro-apoptotic members of the BCL-2 family. Activation of the UPR stress sensors PERK, and
possibly ATF6, promotes the transcriptional induction of the transcription factor CHOP, which downregulates
the anti-apoptotic protein BCL-2 and induces GADD34. In addition, the UPR controls the transcriptional
upregulation of BH3-only proteins (i.e., PUMA, PUMA and NOXA) possibly through p53, CHOP, and ATF4. BIM
protein levels can be regulated by phosphorylation, ubiquitination, and proteasomal degradation. The BH3-only
protein BID also activates apoptosis when it is cleaved by caspase-2. In addition, active IRE1␣ also binds
TRAF2, leading to the activation of the pro-apoptotic kinases JNK and ASK.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1225
THE UNFOLDED PROTEIN RESPONSE
cytosol. As the reader will notice, there are striking differences in the way IRE1 signals in yeast versus mammalian
cells.
A. Mechanism of IRE1␣ Activation and
Stress Sensing
Many other studies have also explored the impact of the
binding of human IRE1␣ to BiP. In contract to yeast IRE1p,
recombinant fragments of the luminal domain of IRE1␣ do
not interact with unfolded proteins in a cell-free system
A recent report provides a new interpretation for the role of
BiP in IRE1p activation. Careful kinetic analysis of IRE1p
signaling in a mutant yeast strain where IRE1p partially
binds BiP revealed a higher susceptibility to undergo activation under mild or low ER stress conditions (143). Remarkably, the kinetics of IRE1p inactivation were significantly delayed in the IRE1p mutants. The authors proposed
a model where three pools of IRE1p exist, an inactive subpopulation in equilibrium with an active unfolded proteinbound pool and a third inactive set sequestered by BiP for
inactivation (FIG. 6D) (138, 143). Thus BiP binding to or
release from IRE1p is not instrumental for activating the
UPR as previously proposed, but it may modulate the sensitivity and dynamics of IRE1p activity, adding more complexity to our understanding of IRE1p signaling. Finally,
two recent, elegant studies suggested that the purpose of
IRE1p auto-phosphorylation is to turn off IRE1p under
conditions of prolonged ER stress rather than to activate it
(20, 157). Inactivation of the IRE1p phosphorylation site
leads to prolonged activation of IRE1p, chronic ER stress,
and decreased yeast viability. Although IRE1␣ is an essential component of the mammalian UPR, structure-functional analysis of its phosphorylation sites in mammals is
far from complete.
B. Cluster Formation by IRE1
Analysis of the tridimensional structure of the cytosolic domain of IRE1p also revealed interesting insights about its
mechanism of signaling (82, 93). Peter Walter’s group was
able to determine the structure and assembly of IRE1p oligomers and observed an unexpected high-order rod-shaped
organization (82). This oligomeric assembly is critical for
FIGURE 6. ER stress-sensing mechanism by IRE1␣. Several models are proposed to explain IRE1␣ activation by the presence of unfolded
proteins at the ER lumen. These models may also operate in the control of PERK activation. A: the indirect recognition model proposes that IRE1␣
is maintained in a repressed state through an association with BiP. Upon ER stress, BiP dissociates to bind unfolded proteins, leading to the
spontaneous dimerization of IRE1␣ and activation of its RNase domain. In this case BiP operates as the “ER stress sensor.” B: a direct
recognition model was proposed from studies in yeast. In this case unfolded proteins may directly bind to the luminal domains of IRE1p stabilizing
the structure of the dimer. C: a hybrid recognition model proposes that both BiP dissociation and peptide binding cause sensor activation. In this
case, BiP may help to place the unfolded proteins into the binding pocket of IRE1␣. D: a new model was proposed from studies in yeast. Three
pools of IRE1p may exist: an inactive subpopulation in equilibrium with an active unfolded protein-bound pool and a third inactive set sequestered
by BiP for inactivation. In this model, BiP binding to or release from IRE1p does not activate the UPR, but it may adjust the sensitivity and dynamics
of IRE1p activity.
1226
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Many different models have been proposed to explain the
mechanism of IRE1␣ activation. The initial model suggests
that under normal conditions, the ER chaperone BiP binds
to the luminal domain of IRE1␣ or the yeast homolog
IRE1p, maintaining the protein in an inactive state as a
monomer (13, 76) (FIG. 6A). Conversely, in cells undergoing
ER stress, BiP is released and binds to unfolded proteins.
This event allows IRE1␣ multimerization and autophosphorylation, activating the RNase domain through a putative conformational change (FIG. 6A). Unexpectedly, mutagenesis analysis of the BiP binding site did not alter the
ability of IRE1p to detect the accumulation of misfolded
proteins, although it ablated BiP (Kar2 in yeast) binding
(77). Additional information about the possible mechanism
of IRE1␣/IRE1p activation was provided by structural
studies of the ER luminal domain of yeast and human IRE1
proteins. Analysis of the yeast IRE1p structure through
bioinformatic and mutagenesis analysis suggested a model
where misfolded proteins may actually bind the NH2-terminal region of IRE1p, promoting its oligomerization
through a structure similar to an MHC groove (FIG. 6B)
(23). In this scenario, misfolded proteins may directly bind
to the luminal region of yeast IRE1p. Although this model
was not directly tested in the study, the idea was reinforced
by a study using recombinant luminal domain of yeast
IRE1p, observing an association with unfolded proteins in a
cell-free system (75). IRE1p activation was then proposed
to be initiated by BiP dissociation from IRE1p, leading to
IRE1p dimerization and cluster formation possibly by binding misfolded proteins (FIG. 6, B AND C) (75). However, no
studies so far have demonstrated the binding of unfolded
proteins to IRE1p in vivo as a mechanism for unfolded
protein recognition and UPR activation in yeast.
(135). This model correlates well with the prediction that
the MHC-like groove observed in the human IRE1␣ ER
luminal domain may not be compatible with the binding of
a peptide as indicated in the crystal structure through in
silico analysis (206). These biochemical data suggest that
the mechanism of sensing ER stress by yeast and mammalian IRE1 may be different (FIG. 6) (135). These limited
biochemical observations highlight the need for more protein-protein interaction studies to fully address the possible
direct impact of the MHC-like groove of IRE1␣ on the
activation of this stress sensor.
HETZ ET AL.
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
1227
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
THE UNFOLDED PROTEIN RESPONSE
IRE1p signaling because different forms of IRE1p dimers
may position the kinase domain for trans-autophosphorylation, generating the RNase active site. Interestingly, the
authors also predicted that this oligomeric assembly may
also generate an additional surface for mRNA binding (82).
C. mRNA Targeting to IRE1
Overall, mechanistic differences are proposed for the targeting of XBP1 and HAC1 mRNAs to IRE1␣ and IRE1p,
respectively. In yeast, in nonstressed cells most of the unspliced HAC1 mRNA is cytoplasmic and remains bound to
the ribosome, but it is not translated. Upon induction of ER
stress, the unspliced HAC1 mRNA colocalizes with IRE1p
clusters in an IRE1p-dependent manner (4). In addition,
HAC1 mRNA targeting to IRE1p requires a specific secondary structure of HAC1 mRNA (4). The splicing of XBP1
mRNA also occurs in the cytosol (179).
In mammals, unspliced XBP1 protein (XBP1u) is expressed
but it is very unstable and is degraded by the proteasome,
and hence, it is in general undetectable in normal cells (18,
128). However, it was shown that XBP1u may have a function in targeting of the XBP1u mRNA to the ER membrane
(193) (FIG. 4B). Although unstable, XBP1u could interact
with membranes, and possibly the ER, bringing XBP1 and
IRE1␣ in close proximity. The membrane association of
XBP1u was mediated by the presence of a well-conserved
hydrophobic region at its COOH terminus (193) (FIG. 4A).
Remarkably, a recent study from Kohno’s group (194)
demonstrated that transient ribosomal translational pausing is important for membrane targeting of XBP1u and
further XBP1 mRNA splicing. This process was also mediated by an evolutionarily conserved sequence in the XBP1u
1228
V. XBP1s BIOLOGY AND REGULATION
XBP1 mRNA splicing is a major event mediating UPR responses. Data from gene expression profile analyses indicate that the universe of XBP1s target genes and downstream effects may vary depending on the cell type and the
nature of the stress stimuli. Although XBP1s orchestrates
many essential processes for adaptation to ER stress, it is
only recently that studies have uncovered possible regulatory effects at the posttranslational level, in addition to the
interaction with other important transcription factors in the
control of gene expression. This emerging topic is discussed
below.
A. XBP1-Dependent Transcriptional
Reprogramming
As mentioned, XBP1s regulates a subset of UPR-induced
genes that participate in folding, quality control, and
ERAD. XBP1s target genes initially identified in mammalian MEF cells were chaperones such as p58IPK, ERdj4,
HEDJ, and the protein disulfide isomerase PDI-P5; the
ERAD-related gene EDEM; and genes involved in glycosylation such as RAMP4 (91). Interestingly, in this study
XBP1s did not affect the upregulation of classical UPRtarget genes such as Grp78/BiP and Grp94. Other studies in
plasma cells confirmed the role of XBP1 in secretory cell
function (164). In terminally differentiated B cells, additional XBP1s target genes were identified that operate in
protein targeting to the ER, ER translocation of proteins,
folding, the ERAD pathway, glycosylation, and vesicular
trafficking through the secretory pathway (164).
Interestingly, gene expression profile analysis in neurons
indicates that XBP1s may control a distinct set of genes in
different cell types (68). We and others have also investigated the impact of XBP1 in the expression of target genes
in neuronal cultures, and identified Grp58, PDI, and Herp
(73), as well as GABAergic markers as XBP1s target genes
(44). Using genome-wide promoter binding assays, another
study described a network of genes regulated by XBP1 using cultures of skeletal muscle and B cells. A core group of
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Other studies suggested that IRE1␣ predominantly forms
dimers upon activation in mammalian cells, in contrast to
PERK activation that is associated with the generation of
high-molecular-weight complexes (13). Structural studies
of the cytosolic domain of human IRE1␣ indicate the presence of dimeric structures, not large oligomers (2, 93).
However, a recent study using overexpression of a GFPtagged form of IRE1␣ indicates that mammalian IRE1␣
also oligomerizes in the ER membrane, correlating with the
onset of IRE1␣ phosphorylation and XBP1 mRNA splicing
(94). The authors suggested that the kinase and RNase domains activate cooperatively, containing more than four
IRE1␣ molecules in the complex for activation (94). Inactivation of IRE1␣ over time is associated with the dissolution
of IRE1␣ clusters, IRE1␣ dephosphorylation, correlating
with a decline of XBP1 mRNA splicing (94). Assembly of
higher order IRE1␣ clusters may represent a conserved
mechanism for its signaling. Nevertheless, all experiments
were performed in an overexpression system, and it remains
to be determined if endogenous IRE1␣ clusters in physiological and/or pathological models of ER stress.
COOH-terminal region (194). In contrast to the yeast
study, IRE1␣ expression is not necessary for the colocalization of the XBP1 mRNA with the ER membrane. Only two
groups have addressed the possible mechanism of mRNA
targeting to IRE1 in the cytosol. More studies are needed to
understand this important event and to define its relevance
in vivo. It is interesting to note that previous studies using
XBP1-deficient animals described a hyperactivation of
IRE1␣ in liver and intestinal tissue associated with splicing
of the truncated XBP1 mRNA (70, 89), suggesting that
expression of a functional XBP1u is not absolutely required
for splicing.
HETZ ET AL.
genes were confirmed as targets of XBP1s that are related to
secretory pathway function and folding (1). This screen also
identified a group of unexpected targets that relate XBP1 to
diseases affecting the brain and muscle, in addition to genes
related to DNA damage and repair. Overall, one may propose that XBP1s regulates a broad array of genes involved
in almost every aspect of ER function and physiology. Based
on the variability observed in most gene expression profile
analyses, further studies are required to define the universe
of XBP1 target genes and to identify the stimuli (pathological and physiological) that modulate them.
B. XBP1s Transcriptional Partners
and Regulation
Other reports suggest that p300/CBP-associated factor
(PCAF) interacts with XBP1s through its COOH-terminal
domain, which may be relevant for host-virus interactions
between a cellular factor, XBP1, and the transcriptional
regulation of the HTLV-1 virus (86). XBP-1s also binds
estrogen receptor ␣ in a ligand-independent manner (32).
However, the relevance of these interactions in vivo is still
unclear.
Posttranslational modifications of XBP1s were recently
proposed to control its activity as a transcription factor
(FIG. 4B). XBP1s is a target of acetylation and deacetylation
mediated by p300 and SIRT1, respectively (183). p300 increases acetylation and protein stability of XBP1s and enhances its transcriptional activity (183). In addition, XBP1s
is SUMOylated, mainly by PIAS2 (protein inhibitor of activated STAT2) at two lysine residues located in the
Another point of regulation was proposed at the level of
XBP1s degradation, where XBP1u markedly accumulates
after prolonged ER stress and forms a heterodimeric complex with XBP1s that is rapidly degraded by the proteasome
(197). This regulatory loop may help to turn off downstream UPR responses (FIG. 4B). This model remains to be
confirmed.
C. XBP1 and Organelle Biogenesis
In activated B cells, induction of XBP1s results in an increase of ER and Golgi content (164). The effects of XBP1s
on organelle biogenesis are also observed in other organelles including lysosomes and mitochondria as evidenced by
an increase in cell size (164). Consistent with these in vitro
phenotypes were the effects observed in vivo when XBP1
was deleted in exocrine cells of the salivary glands, pancreas, intestinal Paneth cells, and gastric epithelial mucous
neck cells. Loss of XBP1 in these tissues resulted in a massive disorganization of the elaborate ER network normally
present in these cell types and subsequent failure of cell
development (60, 90).
It is still unknown how ER and Golgi expansion is induced
under conditions of ER stress. The main barrier in identifying a mechanism arises from the fact that XBP1s target
genes identified to date do not include major genes related
to membrane phospholipid biosynthesis, with the exception
of Chkb, which is involved in the biosynthesis of phosphatidylcholine (164, 168, 169).
VI. ADDITIONAL IRE1␣ DOWNSTREAM
SIGNALING COMPONENTS
In addition to upregulating UPR target genes, mammalian
IRE1␣ signals through additional pathways including c-Jun
NH2-terminal kinase (JNK) and NF-␬B. In addition, a new
function for IRE1␣, IRE1-mediated or regulated decay
(RIDD), has recently been described to exist in both Drosophila and mammalian cells. Here, IRE1 degrades many mRNAs,
some of which encode secretory pathway-related proteins.
These XBP1-independent signaling events are proposed to
modulate a vast spectrum of physiological processes ranging from apoptosis/survival, macroautophagy, proliferation, and metabolism, to inflammatory processes. This is an
active area of research, and recent work has begun to uncover the detailed mechanisms by which IRE1␣ governs
these pathways. Additional work is directed to understanding their relevance in adaptation to stress in vivo.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1229
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Combinatorial interactions among transcription factors are
critical to directing gene expression in a tissue-specific manner. Despite the fundamental role of XBP1 in UPR responses, current knowledge of the regulation of XBP1 activity is limited. Some studies indicate a specific requirement
for XBP1 expression in the transcriptional activity of ATF6f
through the formation of heterodimers (192), although
XBP1s was also proposed to operate mostly as a homodimer in the control of transcription (192). Recent studies identified an interaction between the p85␣ regulatory
subunit of phosphatidylinositol 3-kinase (PI3K) with
XBP1s in an ER stress-dependent manner (141, 189). This
physical association is relevant for metabolic control in diabetes models (141, 189). In addition, XBP1s was proposed
to negatively control the expression levels of the transcription factor Forkhead box O1 (FOXO1) through a physical
interaction, which also modulated glucose metabolism
(207). These three studies defined the impact of XBP1 interaction partners at the biochemical level in addition to
addressing their physiological impact in vivo. Future efforts
are needed to uncover the possible impact of FOXO1 and
p85␣ on adaptation to protein folding stress in more classical models of ER stress.
COOH-terminal transactivation domain (21). Ablation of
these SUMOylation events significantly enhances the transcriptional activity of XBP1s (21) (FIG. 4B). Although these
preliminary findings are interesting, it is still not known if
XBP1s activity is altered by posttranslational modification
under conditions of ER stress.
THE UNFOLDED PROTEIN RESPONSE
A. Control of Stress Kinases and Alarm
Signaling Pathways
B. Regulation of Autophagy
IRE1␣ controls the levels of macroautophagy possibly
through the activation of JNK under ER stress conditions
(25, 133) and also by proteasome inhibition (33). Macroautophagy, here referred to as autophagy, is a survival pathway essential for nutrient starvation conditions through the
recycling of intracellular components (85, 121). It has been
speculated that autophagy may serve as a mechanism to
eliminate damaged organelles and abnormal protein aggregates under ER stress conditions (10, 25, 108). Interestingly, an initial report indicated that activation of autophagy by ER stress in MEFs is dependent on the kinase
domain of IRE1␣, and not affected by the RNAse/XBP1
signaling branch (133). An RNAi screen using fly cells revealed that knocking down XBP1 or its target genes increases basal autophagy levels in the absence of any stress
(6). We recently reported that knocking down XBP1 in
neuronal cells leads to increased basal autophagy flux without any additional stimuli (54). Similar observations were
reported in the central nervous system of xbp1-deficient
mice (54). A major XBP1s-target gene includes EDEM1, an
essential component for ERAD. The impairment of ERAD
activity by XBP1 deficiency was associated with the enhancement of autophagy in neurons. In this scenario, accumulation of abnormally folded proteins at the ER due to
ERAD impairment may operate as the signal to induce autophagy (115).
C. ER-Associated Degradation
As mentioned, some XBP1s target genes are related to the
ERAD pathway and the ER translocon, including HERP,
EDEM, and Sec61. A protein-protein interaction screen revealed a physical association between the ubiquitin specific
protease (USP) 14 and IRE1␣ (125). Interestingly, IRE1␣
1230
D. IRE1␣-Mediated mRNA Decay
Attempts to identify new substrates of IRE1p (132) or
IRE1␣ (129) RNAse activity yielded only HAC1 and XBP1
mRNAs as positive hits. However, another study revealed
that active IRE1␣ in insect cells controls the degradation of
mRNAs of genes encoding ER proteins that are predicted to
be difficult to fold under stress conditions (55, 56). A subset
of genes was shown to be downregulated during ER stress
in an IRE1␣-dependent and XBP1-independent manner,
which were proposed to be direct targets of the IRE1␣ ribonuclease activity (55, 56). The authors speculated that
the selective mRNA degradation by IRE1␣ occurs in a dynamic way, where the misfolding of a nascent protein during its translation may locally activate IRE1␣’s RNase domain to degrade mRNAs being translated (FIG. 7). Two
additional studies confirmed the occurrence of IRE1␣-dependent mRNA decay in mammalian cells (41, 55). Interestingly, artificial dimerization of IRE1␣ in the absence of
ER stress did not trigger mRNA decay, but initiated XBP1
mRNA splicing, suggesting that these two functions of
IRE1␣ are regulated by different factors (55). This alternative function of IRE1␣ may operate to selectively decrease
the production of proteins that challenge the ER at the
folding level and hence alleviate stress. These three reports
used cell-based assays to uncover IRE1␣-dependent mRNA
decay. It remains to be determined if this pathway has any
physiological relevance in vivo in the context of ER stress.
Interestingly, the reports describing IRE1␣-dependent
mRNA decay suggested that the pool of mRNAs targeted
by IRE1␣ depends on the cell type analyzed and not the
nucleotide sequence of the mRNA. The authors failed to
find any consensus sequence for cleavage in all of the RNAs
identified after diverse bioinformatic analyses. In contrast, a
recent study further investigated a possible mechanism for
the recognition of target mRNAs by IRE1␣ in vitro using a
recombinant IRE1␣. The authors employed a combination
of an in vitro cleavage assay with an exon microarray analysis, in addition to a genome-wide screening for IRE1␣
cleavage targets (136). Thirteen novel mRNAs were identified as candidate targets of IRE1␣. Sequence analysis suggested the presence of a putative consensus sequence that
when accompanied by a stem-loop structure is associated
with IRE1␣-mediated cleavage (136). These observations
still need to be corroborated in living cells.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
IRE1␣ controls the initiation of several downstream signaling pathways in addition to processing XBP1 mRNA (FIG.
2). The cytosolic domain of activated IRE1␣ recruits the
adaptor protein TNFR-associated factor 2 (TRAF2), which
then activates the apoptosis signal-regulating kinase 1
(ASK1) pathway (131, 180). Other reports indicate that
IRE1␣ may also initiate the activation of stress pathways
downstream of p38, ERK (130), and NF-␬B (59). Cellbased studies suggested that these effects were mediated by
the binding of the SH2/SH3 containing adaptor proteins
Nck and the inhibitor ␬B kinase, respectively. However, the
possible impact of these downstream UPR signaling
branches in the context of ER stress is still not well defined,
and most of the reports monitor these kinases as stress
markers only.
interacts not only with USP14, but also with other ERAD
components including DERLIN-1, DERLIN-3, SEL1, and
HRD1 (125). These data suggest that IRE1␣ may form a
protein complex with the ERAD machinery. However, a
limitation of this study was the reliance on in vitro experiments using cell lines and protein overexpression. The functional impact of these interactions remains to be established.
HETZ ET AL.
VII. THE UPROSOME: MODULATION OF
IRE1␣ ACTIVITY BY COFACTORS
Although IRE1␣ and PERK ER luminal stress-sensing domains are structurally similar and functionally interchangeable (105), the kinetics of IRE1␣ and PERK signaling are
very different. This fundamental difference in their temporal signaling patterns is proposed to have a substantial impact on cell fate decisions that balance the rate of adaptation/survival to elimination of damaged cells by apoptosis
under stress conditions (191). These differences may now
be explained in part by the discovery of novel specific
regulators of IRE1␣ that modulate the downstream outcomes of its signaling. These regulators control the rate
of IRE1␣ activation/inactivation possibly through the
formation of a dynamic scaffold referred to conceptually
as the UPRosome. In this section we discuss in detail
recent findings that have uncovered unanticipated regulators of IRE1␣ signaling.
A. Positive Regulation of IRE1␣ Signaling by
Apoptosis-Related Proteins
Accumulating evidence indicates that IRE1␣ activation is
specifically regulated by a set of different interaction partners that may determine the threshold of activation and
inactivation (FIG. 8). We have reported that IRE1␣ signaling
is induced by the expression of some pro-apoptotic BCL-2
family members such as BAX and BAK (50). BAX and BAK
expression at the ER modulates the intensity of IRE1␣ signaling but does not alter PERK signaling (50). This regulation is proposed to be mediated by the formation of a protein complex between the cytosolic domain of IRE1␣ and
BAX/BAK (FIG. 3). In addition, BAX and BAK modulated
IRE1␣ signaling in vivo in liver upon ER stress induction
(50). Similarly, another report suggested that the enforced
expression of the pro-apoptotic BH3-only proteins BIM
and PUMA at the ER membrane triggers the activation of
the JNK pathway in an IRE1␣- and BAK-dependent manner (78).
The expression of the pro-apoptotic protein ASK1-interacting protein 1 (AIP1) also increases the amplitude of IRE1␣
signaling as demonstrated in cellular and in vivo models of
ER stress (106). AIP1 expression did not affect the signaling
of the PERK pathway, ruling out possible general effects on
protein folding at the ER lumen (106). These data suggest
an alternative function of certain pro-apoptotic genes in the
regulation of early UPR signaling events, in which they play
a bifunctional role in cell death (late event) and adaptation
to stress (early event) (103) (FIGS. 5 and 8). It still remains
to be determined if all of these IRE1␣ regulators are part of
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1231
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 7. Control of mRNA decay by IRE1␣. IRE1␣ controls the degradation of mRNAs of genes encoding
ER proteins that are predicted to be difficult to fold under stress conditions. The selective mRNA degradation
by IRE1␣ occurs in a dynamic way, where the misfolding of a nascent protein during its translation may locally
activate IRE1␣’s RNase domain to degrade mRNA being translated. This alternative function of IRE1␣ may
operate to selectively decrease the production of proteins that challenge the ER at the folding level and alleviate
stress. A similar mechanism may operate to activate PERK and phosphorylate and inhibit the adjacent
ribosome.
THE UNFOLDED PROTEIN RESPONSE
the same pathway or if they modulate the UPR through
independent mechanisms.
B. Regulation of IRE1␣ by Other Activators
IRE1␣ signaling is also instigated by the expression of the
ER-located protein-tyrosine phosphatase 1B (PTP-1B) in
cellular (38) and animal models (31). Similar to AIP1 and
BAX/BAK, PTP-1B deficiency does not affect PERK-related
signaling in cell culture models. The cytosolic chaperone
heat shock protein 72 (Hsp72) was recently shown to decrease cell death under ER stress conditions (39). Unexpectedly, Hsp72 enhances XBP1 mRNA splicing and its downstream responses (FIG. 8) (39). Regulation of the UPR by
Hsp72 is mediated by the formation of a protein complex
between Hsp72 and IRE1␣. Remarkably, Hsp72 enhances
the RNase activity of IRE1␣ in a cell-free system, suggesting
direct binding and regulation of its activity (39). These results provide for the first time an interconnection between
cytosolic chaperones and the UPR. Moreover, the modulation of XBP1 mRNA splicing by Hsp72 had a substantial
impact on the efficiency of protein secretion.
C. Inactivation of IRE1␣
As mentioned, XBP1 mRNA splicing levels are decreased
after chronic or prolonged ER stress. In contrast, PERK
1232
signaling is sustained over time (97), which may negate the
pro-survival effects of the IRE1␣ and XBP1 pathway (98,
144). Correlative data initially indicated that the IRE1␣ and
ATF6 pathways are negatively modulated by the expression
of the ER-located protein BAX inhibitor-1 (BI-1) in vivo (8,
84). Under ischemic conditions in liver and kidney, BI-1deficient mice displayed increased levels of XBP1s, ATF6f,
and JNK phosphorylation, without altering eIF2␣ phosphorylation (8). We reported an unexpected function of
BI-1 in turning off IRE1␣ signaling. BI-1-deficient cells displayed sustained XBP1 mRNA splicing and enhanced
downstream responses (104). Remarkably, a marked alteration was observed in the inactivation phase of IRE1␣ signaling over time in BI-1-deficient cells. The inhibition of
IRE1␣ by BI-1 was validated in vivo in fly and mouse models of ER stress (104) to affect physiological processes
driven by XBP1. The regulatory activity of BI-1 on IRE1␣
was also corroborated in the setting of obesity and diabetes
in vivo (7).
BI-1 interacts with the cytosolic domain of IRE1␣, and this
association can be reconstituted in vitro where BI-1 reduces
the endoribonuclease activity of IRE1␣ in a cell-free assay
(104). The ER-associated RING-type E3 ligase bifunctional
apoptosis regulator (BAR) interacts with BI-1, promoting
its proteasomal degradation (156), which specifically enhances IRE1␣ signaling (FIG. 8) (156).
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
FIGURE 8. The UPRosome: dynamic modulation of IRE1␣ signaling. Under ER stress conditions, several
modulators assemble into the IRE1␣ scaffold to regulate its activity in terms of kinetics, amplitude, and tissue
specificity. IRE1␣ modulates XBP1 mRNA splicing, mRNA decay, and the activation of stress kinases (alarm
genes) through binding to several adapter proteins. This signaling platform is termed the UPRosome and may
indicate the formation of clusters of foci at the ER. Several factors, including PTP-1B, AIP1, HSP72, BAX, and
BAK, increase the amplitude of IRE1␣ signaling. After prolonged ER stress, IRE1␣ is turned off to remain in a
latent state, a process modulated by an interaction with BI-1 and possibly the phosphatase P2P2A in complex
with RACK1. IRE1␣ activation is also related to the formation of dynamic clusters or multimers formed by
several dimers (n).
HETZ ET AL.
Another study indicates that IRE1␣ is specifically phosphorylated on Ser724 by glucose stimulation (145), and unlike the activation of IRE1␣ by inducers of ER stress, glucose-induced phosphorylation does not cause a shift of the
IRE1␣ protein as detected by Western blot (100, 145) and
does not release the inhibitory interactions with BiP (100).
The scaffold protein receptor for activated C-kinase 1
(RACK1) interacts with IRE1␣ in a glucose-stimulated or
ER stress-dependent manner (145). RACK1 mediates the
assembly of a protein complex containing IRE1␣, RACK1,
and the protein phosphatase 2A (PP2A) (145). This complex regulates the dephosphorylation of IRE1␣ by PP2A
(FIG. 8) (145), thereby inhibiting glucose-stimulated IRE1␣
activation and attenuating IRE1␣-dependent increases in
insulin production.
many physiological processes and diseases. Most of the evidence available points out a key role of XBP1 in mastering
secretory cell function in diverse tissues, in addition to orchestrating lipid metabolism, glucose homeostasis, and inflammatory processes. In agreement with these observations, manipulating IRE1␣ signaling has already proven
efficacious in altering disease severity and progression in
diabetes, cancer, autoimmunity, neurodegeneration, and
other pathologies in rodent models (see TABLE 1). In the
next section we discuss studies that have defined the impact
of the UPR in vivo.
D. IRE1p Allosteric Site
Initial studies of mice with deficiencies in ER-signaling components revealed the function of specific pathways in various organs and tissues. In mice, IRE1␣ inactivation results
in widespread developmental defects leading to embryonic
death at 12.5 days of gestation (201). Analysis of IRE1␣
conditional knockout mice revealed that the early embryonic lethality of the germline knockout was caused by the
loss of IRE1␣ in the placenta (66). Gene expression studies
in IRE1␣- and XBP1-deficient placenta suggested that the
IRE1/XBP1 pathway contributes to the placental expression of the carcinoembryogenic antigen (CEA) family of
proteins (134). The role of these proteins in the placenta is
unclear, and it is unknown whether CEA expression by the
IRE1/XBP1 pathway is required to sustain placental functions. The placental trophoblast produces many secretory
molecules including lactogens and growth factors; it is
therefore possible that the placental defects observed in
IRE1␣-deficient animals are caused by impaired secretion
of factors supporting embryonic development. Interestingly, the deletion of IRE1␣ under the control of the Mox2
promoter leads to viable mice that are born at near-Mendelian ratios (66). In these mice, CRE expression and subsequent IRE1␣ deletion are effective in all epiblast-derived
cells, leading to IRE1␣ deficiency in virtually all embryonic
and adult cells except extraembryonic tissues such as the
placenta, demonstrating that aside from extraembryonic
tissues, IRE1␣ is dispensable for proper embryonic development.
E. IRE1␣ Stability
In addition to the regulation of IRE1␣ RNAse activity, its
protein stability is also controlled, which may affect the
amplitude of UPR responses. HSP90 interacts with the cytosolic domain of IRE1␣, and inhibition of HSP90 interfered with the association of HSP90 and IRE1␣. Dissociation of HSP90 and IRE1␣ leads to its degradation by the
proteasome (111). HSP90 also regulates the stability of
many other protein complexes having an important role in
cell signaling. It remains to be determined if HSP90 regulates the dynamics of the IRE1␣ interactome. In addition,
the impact of HSP90 on IRE1␣ stability needs to be confirmed in other cell types and in vivo.
VIII. ROLE OF THE IRE1/XBP1 PATHWAY
IN ORGAN PHYSIOLOGY
Generation of genetically modified mice has uncovered fundamental functions of the IRE1␣/XBP1 axis of the UPR in
While both IRE1␣ and XBP1 are partners that function in
the same pathway, early studies examining XBP1-deficient
mice revealed phenotypes distinct from IRE1 deletion. Inactivation of XBP1 results in embryonic lethality at 12–13.5
days of gestation caused by severe liver hypoplasia and a
resulting fatal anemia (148). To rescue embryonic death,
selective expression of an XBP1 transgene in liver of XBP1deficient mice was generated using a liver-specific promoter
(88). Mice lacking XBP1 in virtually all organs except the
liver died shortly after birth from a severe impairment in the
production of pancreatic digestive enzymes leading to hypoglycemia and death (88). The expansion of the ER in
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1233
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Overall the data described in the previous sections suggest
that IRE1␣ is actively regulated by the binding of cofactors
that modulate its enzymatic activity. It is not known if all
these regulators (i.e., BAX, BAK, Hsp72, BI-1, RACK1,
AIP1, etc.) bind to the same IRE1␣ domain, and how this
interaction relates to IRE1␣ enzymatic activity at the structural level. Interestingly, a pharmacological screen identified the existence of a possible allosteric site on yeast IRE1p
(190). The flavonol quercetin was shown to activate the
RNase domain in vitro and potentiate activation by ADP, a
natural ligand that binds to the IRE1p nucleotide-binding
cleft (190). Interestingly, enzyme kinetic studies and the
visualization of the structure of a cocrystal of IRE1p bound
to ADP and quercetin identified a new ligand-binding
pocket (190). It remains to be determined if this possible
allosteric site is relevant for the regulation of IRE1p in physiological conditions and if it is functional in mammalian
IRE1␣.
A. Overlapping But Unique Functions of
IRE1 and XBP1 In Vivo
THE UNFOLDED PROTEIN RESPONSE
Table 1. Diseases and defective genes/proteins
Defective
Gene/Protein
Disease
Ulcerative colitis/
Crohn’s disease
Diabetes
Model
Phenotype
Reference
Nos.
XBP1
UPR regulator
Mouse deficiency in the
intestine
Spontaneous enteritis/increased susceptibility
to DSS colitis
70
XBP1
UPR regulator
Polymorphisms in humans
Increased susceptibility to inflammatory bowel
disease
70
IRE1␤
UPR regulator
Mouse deficiency
Increased susceptibility to DSS colitis
AGR2
ER-resident protein
Mouse deficiency
Spontaneous enteritis/increased susceptibility
to DSS colitis
S1P (MBTPS1)
UPR regulator disrupts
ATF6 activation
Hypomorphic mutation in mice
Increased susceptibility to DSS colitis
HLA-B27
ER-resident protein
Expression of a misfolding-prone
protein
Spontaneous colitis, spinal inflammation
PERK
UPR regulator
Human mutations
Infantile diabetes
PERK
UPR regulator
Mouse deficiency
Diabetes mellitus and exocrine pancreatic
insufficiency
XBP1
UPR regulator
Haploinsufficiency
Insulin resistance and type 2 diabetes on highfat diet
139
WSF1
ER-resident protein
Human mutations
Wolfram syndrome, diabetes insipidus,
neurodegeneration
152
Insulin
Secreted protein
Human mutations causing
misfolding
Neonatal diabetes
172
CRCT2 (TORC2)
UPR regulator
Mouse deficiency
Improved insulin sensitivity
Seipin (BSCL2)
ER-resident protein
Human mutations
Lipoatrophy, insulin resistance,
hypertriglyceridemia, and mental
retardation
12
203
16
178
30
42, 202
185, 186
62
ATF6
UPR regulator
Human polymorphisms
Increased susceptibility to type 2 diabetes
p58IPK
UPR regulator
Mouse deficiency
Type 1 diabetes
119, 175
EIF2S1
Protein synthesis regulator
Mouse deficiency
Glucose intolerance resulting from reduced
insulin secretion
XBP1
UPR regulator
Mouse deficiency in the brain
More resistant to a mouse model of ALS
PERK
UPR regulator
Mouse heterozygous
More susceptibility to develop experimental
ALS
184
ATF6
UPR regulator
Mouse deficiency
More susceptibility to loss of dopaminergic
neurons in a mouse model of Parkinson’s
disease
167
CHOP
UPR eferter
Mouse deficiency
More resistant to loss of dopaminergic
neurons in a mouse model of Parkinson’s
disease
184
BAP (SIL1)
ER-resident protein, Bip
regulator
Human mutations
Marinesco-Sjogren syndrome, an autosomal
recessive disorder characterized by
cerebellar ataxia, progressive myopathy,
and cataracts
BAP (SIL1)
ER-resident protein, Bip
regulator
Mouse deficiency
Adult-onset ataxia with cerebellar Purkinje cell
loss
87
161
54
3, 163
204, 205
ER, endoplasmic reticulum; UPR, unfolded protein response; DSS, dextran disulfide sulfate; ALS, amyotrophic
lateral sclerosis.
salivary glands and pancreatic exocrine cells was severely
impaired resulting in a complete disorganization of the ER
network and impaired production and release of zymogen
granules (88), demonstrating the crucial role of XBP1 in the
development of highly secretory exocrine cells. Interestingly, mice in which IRE1␣ deficiency is limited to epiblastderived cells have normal salivary glands and only a partial
defect in the pancreas (65). Because IRE1␣ is believed to be
essential for XBP1 activation, it is unclear why IRE1␣ deficiency does not mirror the phenotypes observed in XBP1deficient mice. Differences in experimental conditions such
as background strain and usage of different tissue-specific
Cres may be partly responsible. More likely is the possibility
that these differences indicate that IRE1␣ has functions independent of XBP1 and, vice versa, that XBP1 has func-
1234
tions independent of IRE1␣. IRE1␣ is known to engage
multiple pathways beyond XBP1 activation (51); however,
the activation of XBP1 is believed to be exclusively IRE1␣
dependent. It is therefore possible that some aspects of the
phenotypes observed in XBP1-deficient animals are caused
by the deficiency in the unspliced form of XBP1 that can
bind ATF6 and therefore regulate expression of a subset of
genes independently of IRE1␣. Alternatively, XBP1 could
be activated independently of IRE1␣, although there are no
data that support that idea. Finally, we cannot exclude the
possibility that part of the phenotype observed in XBP1
deficiency is caused by constitutive IRE1 hyperactivation. It
is known for example that IRE1-mediated RNA decay may
promote death of stressed cells (41). Therefore, in the absence of XBP1, stressed cells, unable to cope with the stress,
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Neurodegeneration
Fuction of the Gene
HETZ ET AL.
might activate IRE1-mediated cell death and tissue disorganization. This model would predict more severe abnormalities in XBP1-deficient compared with IRE1␣-deficient animals.
B. XBP1 Function in Secretory Cells
and Lipogenesis
XBP1 is also required for Paneth cell function (70). When
exposed to bacteria or bacterial antigens, Paneth cells become secretory and release a number of antimicrobial enzymes and proteins into the lumen of the crypt, thereby
contributing to maintenance of the gastrointestinal epithelial barrier. XBP1 deletion in intestinal epithelial cells triggered spontaneous enteritis secondary to Paneth cell dysfunction leading to increased susceptibility to induced colitis (70). In agreement with these reports, conditional IRE1␣
deficiency caused structural abnormalities of the pancreatic
acinar and salivary tissues, in addition to attenuated serum
levels of immunoglobulin (65).
XBP1 is also involved in the homeostasis and function of
nonsecretory cells. XBP1 expression in the liver is required
for normal fatty acid and sterol synthesis (37, 89). The
deletion of XBP1 in the liver led to significant decrease of
triglycerides, cholesterol, and free fatty acids without causing fatty liver (89). XBP1 activation upon high-carbohydrate diet feeding triggers the transcription of key lipogenic
genes in hepatocytes, suggesting that XBP1 directly promotes synthesis of lipids in the liver (89). Although liverspecific deletion of IRE1␣ had minor effects on basal liver
physiology (65, 200), the mice developed severe hepatic
steatosis upon ER stress induction, expression of a misfolding-prone human blood clotting factor VIII, or after partial
hepatectomy (200).
C. XBP1 and Immunity
Beyond its role in the maintenance of secretory cells and
lipid metabolism, XBP1 was shown to modulate immune
responses. XBP1 is important for the development and survival of dendritic cells (64) and in the immune response to
challenge by pathogens that activate the Toll-like receptors
(TLRs) (112). Toll-like receptors (TLRs) are single, membrane-spanning receptors that recognize structurally conserved molecules derived from microbes to orchestrate immune responses. In the absence of detectable ER stress,
TLR4 and TLR2 activation by microbial products specifically promotes the phosphorylation of IRE1␣ and the activation of XBP1 (112). IRE1␣ activation by TLR engagement does not induce ER stress target genes, but is required
for optimal and sustained production of proinflammatory
cytokines in macrophages (112). Consistent with these findings, XBP1 deficiency markedly increases bacterial burden
in mice infected with the TLR2-activating pathogen Francisella tularensis. Similarly, infection of Caenorhabditis elegans with pore-forming toxins harboring bacteria leads to
the activation of XBP1 and ATF6 to promote immune defense (14). The functional synergy demonstrated between
TLR activation and classic pharmacological stressors like
tunicamycin in IRE1 activation suggests that discovery of
nontoxic pharmacological ER stressors may be useful in
augmenting vaccine efficacy. TLR signals also actively repress the other UPR branches, a strategy that may prevent
prolonged, damaging ER stress (173). Another study demonstrated that C. elegans infected with Pseudomonas
aeruginosa activate IRE1 and XBP1 through the innate immune kinase PMK-1 (151). In this model it was shown that
XBP1 loss of function decreases the survival of infected
worms, probably due to aberrant activation of PMK-1
(151).
Altogether these studies clearly demonstrate that XBP1 and
IRE1 are key in the maintenance of various physiological
processes including lipid metabolism, maintenance of secretory cell function, and innate immunity. A better understanding of the mechanisms and specific roles of the various
ER-signaling pathways in these processes will be key in
appreciating the link between stress responses and physiological processes.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1235
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
The role of XBP1 in the maintenance and differentiation of
secretory cells in the salivary gland and exocrine pancreas of
XBP1-deficient mice is consistent with its role in ER/Golgi
biogenesis and phospholipid synthesis (164, 168, 169). Indeed, the first evidence that XBP1 was involved in the differentiation of secretory cells came 10 years ago with the
finding that XBP1-deficient B cells are unable to differentiate into antibody-producing plasma cells (149). Antibody
secretion in vivo in response to antigenic challenge is impaired in XBP1-deficient mice, an activity later shown to be
directly dependent on XBP1 splicing in stimulated B cells
(63, 177). Interestingly, XBP1 activation in B cells lacking
IgM is still present (58), suggesting that secretory cells activate XBP1 as a part of the differentiation program rather
than as a consequence of massive immunoglobulin synthesis and secretion. Of note, IRE1␣ deficiency in B cells led to
a much earlier block in B-cell differentiation at the pre-B cell
stage, emphasizing the lack of complete concordance in
pathway components.
The XBP1/IRE1 pathway in the liver may be regulated by
circadian rhythms. XBP1 and IRE1␣ have been shown to be
activated rhythmically every 12 h in hepatocytes (24). Animals lacking a circadian clock exhibit constitutive activation of the IRE1/XBP1 pathway. These findings are consistent and correlate with asynchronous expression of enzymes involved in lipid metabolism and triglyceride
accumulation in the liver (24).
THE UNFOLDED PROTEIN RESPONSE
IX. ACTIVATION OF THE IRE1/XBP1
PATHWAY AND DISEASE PATHOLOGY:
FROM CANCER TO ATHEROSCLEROSIS
A. Cancer
Although the engagement of the ER stress response is essential to adapt to alterations in the ER, abnormal and sustained ER-stress can contribute to development of pathologies such as neurodegenerative diseases. Moreover, the ER
stress response may modulate the pathological state of preexisting diseases such as some cancers.
Studies have suggested that IRE1 and XBP1 are involved in
cancer progression. XBP1 overexpression has been demonstrated in numerous human cancers such as breast cancer,
hepatocellular carcinoma, and pancreatic adenocarcinomas
(81). Transformed MEFs or HT1080 that are deficient in
XBP1 have an impaired ability to grow as tumor xenografts
in SCID mice compared with XBP1 proficient cells (154).
Moreover, sustained active XBP1 overexpression in a transgenic mouse model suggested that XBP1 is capable of neoplastic transformation of plasma B cells into multiple myeloma (19). The recent identification of a putative IRE1
RNase inhibitor that displays significant anti-myeloma activity in a model of human multiple myeloma xenografts
(140) further suggests that the IRE1/XBP1 pathway is a
promising target for anti-cancer therapy. Additional IRE1␣
inhibitory compounds have also been recently described
(182).
Folding problems in the ER can compromise the traffic
and function of a variety of proteins resulting in the
degradation of the unfolded protein and/or the activation
of ER stress. Many human diseases are associated with
perturbations in the ER machinery and the accumulation
of unfolded proteins in the ER (142). At least some of
these pathologies may involve the engagement of the
IRE1/XBP1 pathway.
B. Neurodegenerative Diseases
Multiple studies suggest that the UPR may be involved in
the modulation of neurodegenerative diseases (114). A
common feature of many neurodegenerative diseases is the
1236
C. Diabetes
ER stress may be involved in the development of congenital
diabetes. Neonatal diabetes, for example, is a rare genetic
disorder developing in the first weeks of life characterized
by insulin-demanding hyperglycemia (172, 187). An autosomal dominant form of this disease is caused by mutations
in one of the two alleles of the insulin gene. These mutations
cause improper folding of the proinsulin probably leading
to sustained ER stress and ␤-cell loss of function. A similar
mutation affecting mouse insulin in the Akita diabetes
model has been shown to cause insulin misfolding leading
to ␤-cell disruption and diabetes (67). How ER stress affects
the overall integrity of ␤-cells is unclear. IRE1␣ enhances
proinsulin synthesis upon acute exposure to high glucose
concentrations (100). Intriguingly IRE1␣ engagement by
high glucose in ␤-cells does not result in XBP1 mRNA splicing, but correlates with the induction of WSF1. This activation is believed to be beneficial to ␤-cells. In contrast,
chronic exposure of ␤-cells to high glucose causes ER stress
and hyperactivation of IRE1, leading to the suppression of
insulin gene expression (100). Insulin suppression in
stressed ␤-cells has been proposed to be directly caused by
IRE1-mediated degradation of the insulin mRNA (102).
Therefore, IRE1-mediated loss of insulin production may
constitute a hallmark of ER stress-mediated diabetes and
may explain how ER stress mediated by misfolding of one
of the two insulin alleles dramatically contributes to the
development of insulin-demanding hyperglycemia.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
Cancer development is often associated with a range of
cytotoxic conditions like hypoxia, nutrient deprivation,
and pH changes caused by poorly vascularized solid tumor
cells. These conditions trigger a set of cellular stress response pathways including the ER-stress response that
helps the cell to cope with the stress. Many aspects of the
ER-stress response are cytoprotective, and several studies
indicate that this response has a crucial role in tumor
growth (48, 107).
accumulation and deposition of misfolded proteins leading
to decreased neuronal function and viability (61). Upregulation of ER stress markers has been observed in post mortem brain tissues and cell culture models of disorders such
as Parkinson’s disease, amyotrophic lateral sclerosis (ALS),
Alzheimer’s disease, Huntington disease, and CreutzfeldtJacob disease (5, 99, 113). Whether ER stress is a cause or a
consequence of neurodegeneration and how ER stress modulates disease progression are still poorly understood. On
one hand, the ER stress response may be protective and
provide relief in cases of mild injury, while on the other
hand, it could contribute to neuronal toxicity in cases of
sustained stress and continuous accumulation of misfolded
proteins. Consistent with a model in which components of
the ER stress response favor neurotoxicity, XBP1 deficiency
in the nervous system was shown to be protective in a
mouse model of ALS due to an enhanced clearance of mutant SOD1 aggregates by macroautophagy, a cellular pathway involved in protein degradation (54, 127). In contrast,
the specific deletion of XBP1 in neurons has no detectable
effect on the development of the central nervous system and
did not trigger any obvious impairment or enhance the progression of a prion disease model (53). In contrast, PERK
deficiency exacerbated ALS disease progression (184), indicating that defining the participation of the UPR in neurodegeneration is very complex.
HETZ ET AL.
D. Inflammatory Diseases
A growing number of reports have suggested that ER stress
may contribute to inflammation and inflammation-related
diseases (57). Rats expressing a misfolding-prone and ER
stress-promoting human HLA-B27 protein in macrophages
exhibit inflammation in the joints and the intestine (29,
178). Humans with HLA-B27 are at increased risk of developing seronegative spondyloarthropathies such as ankylosing spondylitis (AS), a potentially disabling form of arthritis characterized by spinal inflammation and enthesopathy (174). These observations are consistent with the fact
that activation of ER stress has been associated with hyperinflammatory responses in macrophages. Indeed, recent
findings demonstrate that ER-stressed macrophages are hyperresponsive to TLR stimulation in an XBP1-dependent
manner (112). These findings, in addition to the observation that XBP1 is involved in TLR signaling pathways in the
absence of ER stress (112), support the notion that XBP1 is
a positive regulator of TLR gene induction and inflammatory programs. The observation that ER stress and the
IRE1/XBP1 pathway per se may promote inflammation by
regulating the intensity and duration of inflammatory responses is quite intriguing and directs our attention to a
broad range of diseases that are associated with inflammation and the upregulation of ER stress-responsive genes (57,
112). Among those diseases, cardiovascular diseases and
diseases involving intestinal inflammation are the best characterized.
Increasing evidence indicates that the ER stress response is
activated in atherosclerotic lesions including in macrophages and endothelial cells (120, 173). Various pathological mediators of atherosclerosis can trigger ER stress pathways including oxidative stress, oxysterols, pathological
levels of intracellular lipids such as cholesterol and saturated fatty acids characteristic of diseases, and conditions
associated with obesity (173). Whether ER stress-mediated
outputs such as hyperinflammatory reactions and cell death
contribute to the development of atherosclerosis in vivo is
an exciting question that requires further investigation (57,
173).
The intestinal epithelium is exposed to a diverse array of
pathogens and commensal bacteria as well as numerous
metabolic products derived from the host and the microbial
community. At the same time, the intestinal epithelium secretes via specialized secretory cells such as Paneth cells and
goblet cells antimicrobial and regulatory molecules that are
key in maintaining tissue homeostasis. As such, the intestine
is a key organ where both inflammatory pathways and ER
stress pathways are present and crucial. It is therefore not
surprising that deficiencies in ER stress pathways can lead
to intestinal inflammation (71, 118). IRE1␤ is a homolog of
IRE1␣ mainly expressed in colonic and gastric epithelial
cells whose deficiency is associated with increased susceptibility to dextran sodium sulfate (DSS)-mediated colitis (12).
Similarly, mice with XBP1 deficiency in intestinal epithelium develop a spontaneous enterocolitis and display increased susceptibility to DSS-mediated colitis (70). Moreover, in humans, XBP1 polymorphisms were identified as
risk factors for the human inflammatory bowel diseases
Crohn’s disease and ulcerative colitis (70). Other ER stresscausing mutations have been associated with intestinal inflammation (71, 118). One example is illustrated by the
study of an ER-residing protein disulfide isomerase (PDI)
family member, anterior gradient 2 (AGR2). AGR2 deficiency results in the accumulation of misfolded proteins in
the ER (203). Similarly to XBP1-deficient mice, AGR2 mice
exhibit severe intestinal inflammation. Part of the inflammation observed in XBP1- and AGR2-deficient mice is
probably caused by deficiencies in Paneth cells and goblet
cells; however, it is likely that ER stress per se can intersect
with the immune response and contribute to the excessive,
pathological inflammation observed in these diseases.
X. DISCUSSION
A. The UPRosome as an Integrator of
Physiological and Pathological Stress
Responses
The UPR is a complex signal transduction pathway, essential for the survival and function of specialized secretory
cells. Genetic evidence in different animal models revealed a
vital function of UPR components in the development and
function of plasma B cells, pancreatic exocrine and endocrine cells, and salivary glands. Remarkably, new functions
of the UPR have emerged in other tissues where this pathway modulates lipid and cholesterol levels in addition to
regulating the innate immune system. The UPR also participates in balancing global homeostasis by controlling the
levels of insulin and its consequences in the liver, in addition
to metabolic control at the hypothalamus level. To add
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1237
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
ER stress has also been linked to type 2 diabetes. Obesityinduced ER stress in the liver plays a central role in the
development of insulin resistance and type 2 diabetes by
promoting JNK activity via IRE1␣ and dampening insulin
receptor signaling (139). XBP1⫹/⫺ mice exhibited increased
ER stress and increased susceptibility to develop insulin
resistance upon high-fat diet-induced obesity (139). It has
also been suggested that deficient insulin signaling might
directly affect XBP1 activity by dampening nuclear translocation of active XBP1 in the hepatocytes of obese mice
(141). This defect in nuclear localization of XBP1 may contribute to the inability to cope with increased stress observed in obese mice. Finally, interaction of XBP1 with
other transcription factors may also be important for regulating glucose metabolism and insulin secretion (141, 189,
207).
THE UNFOLDED PROTEIN RESPONSE
more complexity to all these findings, genetic studies targeting specific UPR components indicate that the function and
impact of distinct UPR signaling branches may differ drastically when the same tissue is analyzed. In addition to operating in diverse physiological processes, chronic ER stress
is linked to a variety of diseases related to abnormal protein
folding and ER dysfunction. Thus the UPR is becoming a
relevant target for therapeutic intervention in a wide variety
of disease conditions.
FONDAP Grant 15010006 (to C. Hetz); FONDECYT Grant
3100033 (to D. Rodriguez); Swiss National Science Foundation Grant 31003A_130476 (to F. Martinon); and National
Institute on Aging Grant AI-32412, the Leila and Harold
Mathers Foundation, and an anonymous foundation (to L. H.
Glimcher).
Little is known about the regulation of UPR signaling by
specific stimuli or at the levels of distinct tissues/organs, and
how the kinetics and amplitude of signaling of each UPR
branch are controlled. Since PERK and IRE1␣ share functionally similar luminal sensing domains and they are interchangeable without affecting cytosolic signaling (105), we
speculate that the specific activation of ER stress sensors in
different tissues may be explained by the presence of specific
regulators of their activities. We propose a model where an
intricate signaling platform docks at IRE1␣ and maybe
other UPR stress sensors to fine-tune its activation threshold
to modulate signaling intensity and kinetics of activation/
inactivation. This fine tuning of UPR signaling responses is
particularly relevant for cell fate decisions by controlling
downstream programs that regulate either adaptation to
stress or the initiation of apoptosis to eliminate irreversibly
injured cells. We refer to this regulatory and signaling complex as the UPRosome (52, 103). This scaffold initiates
multiple signaling responses in a highly regulated manner
(FIG. 8). It remains to be determined if PERK and ATF6 are
also regulated by the binding of specific modulators, forming other distinct UPRosomes. Defining the static and dynamic composition of tissue specific UPRosomes is of particular relevance due to the divergent and fundamental roles
of the UPR in cell physiology, in addition to its participation
in many important diseases including cancer, neurodegeneration, diabetes, and autoimmunity. A deeper understanding of how the UPR signals and is regulated may provide
new therapeutic targets to modulate ER stress levels in human disease.
No conflicts of interest, financial or otherwise, are declared
by the authors.
Addresses for reprint requests and other correspondence:
L. H. Glimcher, Dept. of Immunology and Infectious Diseases, FXB Building, Rm. 205, 651 Huntington Ave., Boston, MA 02115 (e-mail: [email protected]); C.
Hetz, Institute of Biomedical Sciences, Faculty of Medicine,
P.O. Box 70086, Univ. of Chile, Independencia 1027, Santiago, Chile (e-mail: [email protected]).
GRANTS
This work was supported by the following: FONDECYT
Grant 1100176, Millennium Institute Grant P09-015-F, Michael J. Fox Foundation for Parkinson’s Research, ICGEB,
Alzheimer’s Disease Foundation, CHDI Foundation, and
1238
REFERENCES
1. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y,
Dynlacht BD. XBP1 controls diverse cell type- and condition-specific transcriptional
regulatory networks. Mol Cell 27: 53– 66, 2007.
2. Ali MM, Bagratuni T, Davenport EL, Nowak PR, Silva-Santisteban MC, Hardcastle A,
McAndrews C, Rowlands MG, Morgan GJ, Aherne W, Collins I, Davies FE, Pearl LH.
Structure of the Ire1 autophosphorylation complex and implications for the unfolded
protein response. EMBO J 30: 894 –905, 2011.
3. Anttonen AK, Mahjneh I, Hämäläinen RH, Lagier-Tourenne C, Kopra O, Waris L,
Anttonen M, Joensuu T, Kalimo H, Paetau A, Tranebjaerg L, Chaigne D, Koenig M,
Eeg-Olofsson O, Udd B, Somer M, Somer H, Lehesjoki AE. The gene disrupted in
Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone. Nature Genet
37: 1309 –1311, 2005.
4. Aragon T, van Anken E, Pincus D, Serafimova IM, Korennykh AV, Rubio CA, Walter P.
Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 457:
736 –740, 2009.
5. Aridor M. Visiting the ER: the endoplasmic reticulum as a target for therapeutics in
traffic related diseases. Advanced Drug Delivery Rev 59: 759 –781, 2007.
6. Arsham AM, Neufeld TP. A genetic screen in Drosophila reveals novel cytoprotective
functions of the autophagy-lysosome pathway. PLoS One 4: e6068, 2009.
7. Bailly-Maitre B, Belgardt BF, Jordan SD, Coornaert B, von Freyend MJ, Kleinridders A,
Mauer J, Cuddy M, Kress CL, Willmes D, Essig M, Hampel B, Protzer U, Reed JC,
Bruning JC. Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesityassociated insulin resistance and glucose intolerance. J Biol Chem 285: 6198 – 6207,
2010.
8. Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci JE, Croxton R,
Krajewska M, Zapata JM, Kupiec-Weglinski JW, Farmer D, Reed JC. Cytoprotective
gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and
ischemia-reperfusion injury. Proc Natl Acad Sci USA 103: 2809 –2814, 2006.
9. Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science 319: 916 –919, 2008.
10. Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4: e423, 2006.
11. Bernasconi R, Molinari M. ERAD and ERAD tuning: disposal of cargo and of ERAD
regulators from the mammalian ER. Curr Opin Cell Biol 23: 176 –183, 2011.
12. Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho JH, West AB, Ron D.
Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. J Clin
Invest 107: 585–593, 2001.
13. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of
BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:
326 –332, 2000.
14. Bischof LJ, Kao CY, Los FC, Gonzalez MR, Shen Z, Briggs SP, van der Goot FG, Aroian
RV. Activation of the unfolded protein response is required for defenses against
bacterial pore-forming toxin in vivo. PLoS Pathog 4: e1000176, 2008.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
ACKNOWLEDGMENTS
DISCLOSURES
HETZ ET AL.
15. Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, Wouters BG, Bell JC.
Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell
Biol 24: 7469 –7482, 2004.
16. Brandl K, Rutschmann S, Li X, Du X, Xiao N, Schnabl B, Brenner DA, Beutler B.
Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proc Natl Acad Sci USA 106:
3300 –3305, 2009.
17. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci
122: 437– 441, 2009.
18. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D. IRE1
couples endoplasmic reticulum load to secretory capacity by processing the XBP-1
mRNA. Nature 415: 92–96, 2002.
19. Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE, Zheng M,
Mani M, Henderson J, Pinkus GS, Munshi N, Horner J, Ivanova EV, Protopopov A,
Anderson KC, Tonon G, DePinho RA. The differentiation and stress response factor
XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11: 349 –360, 2007.
21. Chen H, Qi L. SUMO modification regulates the transcriptional activity of XBP1.
Biochem J 429: 95–102, 2010.
22. Cox JS, Walter P. A novel mechanism for regulating activity of a transcription factor
that controls the unfolded protein response. Cell 87: 391– 404, 1996.
23. Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P. On the mechanism of
sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci USA 102:
18773–18784, 2005.
24. Cretenet G, Le Clech M, Gachon F. Circadian clock-coordinated 12 Hr period rhythmic activation of the IRE1alpha pathway controls lipid metabolism in mouse liver. Cell
Metab 11: 47–57, 2010.
25. Criollo A, Vicencio JM, Tasdemir E, Maiuri MC, Lavandero S, Kroemer G. The inositol
trisphosphate receptor in the control of autophagy. Autophagy 3: 350 –353, 2007.
26. Cullinan SB, Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 279:
20108 –20117, 2004.
27. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct
PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23: 7198 –
7209, 2003.
28. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 116: 205–219, 2004.
29. Delay ML, Turner MJ, Klenk EI, Smith JA, Sowders DP, Colbert RA. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are
associated with Th17 activation in transgenic rats. Arthritis Rheum 60: 2633–2643,
2009.
30. Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3,
encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with
Wolcott-Rallison syndrome. Nature Genet 25: 406 – 409, 2000.
31. Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, Cho YR, Kim JK, Kahn BB,
Neel BG, Bence KK. Liver-specific deletion of protein-tyrosine phosphatase 1B
(PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic
reticulum stress. Diabetes 58: 590 –599, 2009.
32. Ding LH, Ye QN, Yan JH, Zhu JH, Lu QJ, Wang ZH, Huang CF. XBP-1 interacts with
estrogen receptor alpha (ERalpha). Sheng Wu Gong Cheng Xue Bao 20: 332–336, 2004.
33. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171: 513–524, 2007.
37. Glimcher LH, Lee AH. From sugar to fat: how the transcription factor XBP1 regulates
hepatic lipogenesis. Ann NY Acad Sci 1173 Suppl 1: E2–9, 2009.
38. Gu F, Nguyen DT, Stuible M, Dube N, Tremblay ML, Chevet E. Protein-tyrosine
phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress. J Biol
Chem 279: 49689 – 49693, 2004.
39. Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C, Samali A. HSP72 protects cells from
ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a
physical interaction. PLoS Biol 8: e1000410, 2010.
40. Hamman BD, Hendershot LM, Johnson AE. BiP maintains the permeability barrier of
the ER membrane by sealing the lumenal end of the translocon pore before and early
in translocation. Cell 92: 747–758, 1998.
41. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA,
Papa FR. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138: 562–575, 2009.
42. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D.
Diabetes mellitus and exocrine pancreatic dysfunction in perk⫺/⫺ mice reveals a role
for translational control in secretory cell survival. Mol Cell 7: 1153–1163, 2001.
43. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B,
Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress
response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell
11: 619 – 633, 2003.
44. Hayashi A, Kasahara T, Kametani M, Kato T. Attenuated BDNF-induced upregulation
of GABAergic markers in neurons lacking Xbp1. Biochem Biophys Res Commun 376:
758 –763, 2008.
45. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6
is synthesized as a transmembrane protein and activated by proteolysis in response to
endoplasmic reticulum stress. Mol Biol Cell 10: 3787–3799, 1999.
46. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu
Rev Genet 43: 67–93, 2009.
47. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J. Identification of
activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for
heme oxygenase-1 gene regulation. J Biol Chem 276: 20858 –20865, 2001.
48. Healy SJM, Gorman AM, Mousavi-Shafaei P, Gupta S, Samali A. Targeting the endoplasmic reticulum-stress response as an anticancer strategy. Eur J Pharmacol 625:
234 –246, 2009.
49. Hebert DN, Molinari M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol Rev 87: 1377–1408, 2007.
50. Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Antonsson B, Brandt GS, Iwakoshi
NN, Schinzel A, Glimcher LH, Korsmeyer SJ. Proapoptotic BAX and BAK modulate
the unfolded protein response by a direct interaction with IRE1alpha. Science 312:
572–576, 2006.
51. Hetz C, Glimcher LH. Fine-tuning of the unfolded protein response: assembling the
IRE1␣ interactome. Mol Cell 35: 551–561, 2009.
52. Hetz C, Glimcher LH. The UPRosome and XBP-1: mastering secretory cell function.
Curr Immunol Rev 4: 1–10, 2008.
53. Hetz C, Lee AH, Gonzalez-Romero D, Thielen P, Castilla J, Soto C, Glimcher LH.
Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc Natl Acad Sci USA 105: 757–762, 2008.
34. Ellgaard L, Helenius A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell
Biol 4: 181–191, 2003.
54. Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM,
Brown RH, Glimcher LH. XBP-1 deficiency in the nervous system protects against
amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23: 2294 –2306,
2009.
35. Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol
3: E255–263, 2001.
55. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated Ire1-dependent
decay of messenger RNAs in mammalian cells. J Cell Biol 186: 323–331, 2009.
36. Galehdar Z, Swan P, Fuerth B, Callaghan SM, Park DS, Cregan SP. Neuronal apoptosis
induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated in-
56. Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the
unfolded protein response. Science 313: 104 –107, 2006.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1239
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
20. Chawla A, Chakrabarti S, Ghosh G, Niwa M. Attenuation of yeast UPR is essential for
survival and is mediated by IRE1 kinase. J Cell Biol 193: 41–50, 2011.
duction of the Bcl-2 homology 3-only member PUMA. J Neurosci 30: 16938 –16948,
2010.
THE UNFOLDED PROTEIN RESPONSE
57. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic
disease. Cell 140: 900 –917, 2010.
58. Hu CC, Dougan SK, McGehee AM, Love JC, Ploegh HL. XBP-1 regulates signal
transduction, transcription factors and bone marrow colonization in B cells. EMBO J
28: 1624 –1636, 2009.
59. Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH. Autocrine tumor necrosis factor
alpha links endoplasmic reticulum stress to the membrane death receptor pathway
through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2
expression. Mol Cell Biol 26: 3071–3084, 2006.
60. Huh WJ, Esen E, Geahlen JH, Bredemeyer AJ, Lee AH, Shi G, Konieczny SF, Glimcher
LH, Mills JC. XBP1 controls maturation of gastric zymogenic cells by induction of
MIST1 and expansion of the rough endoplasmic reticulum. Gastroenterology 139:
2038 –2049, 2011.
61. Hutt DM, Powers ET, Balch WE. The proteostasis boundary in misfolding diseases of
membrane traffic. FEBS Lett 583: 2639 –2646, 2009.
62. Ito D, Suzuki N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 132: 8 –15, 2009.
64. Iwakoshi NN, Pypaert M, Glimcher LH. The transcription factor XBP-1 is essential for
the development and survival of dendritic cells. J Exp Med 204: 2267–2275, 2007.
65. Iwawaki T, Akai R, Kohno K. IRE1alpha disruption causes histological abnormality of
exocrine tissues, increase of blood glucose level, and decrease of serum immunoglobulin level. PLoS One 5: e13052, 2010.
66. Iwawaki T, Akai R, Yamanaka S, Kohno K. Function of IRE1 alpha in the placenta is
essential for placental development and embryonic viability. Proc Natl Acad Sci USA
106: 16657–16662, 2009.
67. Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, Takeuchi T. Dominant
negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes 52:
409 – 416, 2003.
68. Kakiuchi C, Ishiwata M, Hayashi A, Kato T. XBP1 induces WFS1 through an endoplasmic reticulum stress response element-like motif in SH-SY5Y cells. J Neurochem
97: 545–555, 2006.
69. Kanda H, Miura M. Regulatory roles of JNK in programmed cell death. J Biochem 136:
1– 6, 2004.
70. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins
DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134:
743–756, 2008.
71. Kaser A, Martínez-Naves E, Blumberg RS. Endoplasmic reticulum stress: implications
for inflammatory bowel disease pathogenesis. Curr Opin Gastroenterol 26: 318 –326,
2010.
72. Kaufman RJ. Regulation of mRNA translation by protein folding in the endoplasmic
reticulum. Trends Biochem Sci 29: 152–158, 2004.
73. Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. Proc Natl Acad Sci USA 99: 10671–10676, 2002.
74. Kim H, Tu HC, Ren D, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH.
Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial
apoptosis. Mol Cell 36: 487– 499, 2009.
75. Kimata Y, Ishiwata-Kimata Y, Ito T, Hirata A, Suzuki T, Oikawa D, Takeuchi M, Kohno
K. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and
interaction with unfolded proteins. J Cell Biol 179: 75– 86, 2007.
79. Kondo S, Murakami T, Tatsumi K, Ogata M, Kanemoto S, Otori K, Iseki K, Wanaka A,
Imaizumi K. OASIS, a CREB/ATF-family member, modulates UPR signalling in astrocytes. Nat Cell Biol 7: 186 –194, 2005.
80. Kondo S, Saito A, Hino S, Murakami T, Ogata M, Kanemoto S, Nara S, Yamashita A,
Yoshinaga K, Hara H, Imaizumi K. BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of endoplasmic reticulum stress transducer. Mol Cell Biol 27:
1716 –1729, 2007.
81. Koong AC, Chauhan V, Romero-Ramirez L. Targeting XBP-1 as a novel anti-cancer
strategy. Cancer Biol Ther 5: 756 –759, 2006.
82. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, Stroud
RM, Walter P. The unfolded protein response signals through high-order assembly of
Ire1. Nature 457: 687– 693, 2009.
83. Koumenis C. ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 6:
55– 69, 2006.
84. Krajewska M, Xu L, Xu W, Krajewski S, Kress CL, Cui J, Yang L, Irie F, Yamaguchi Y,
Lipton SA, Reed JC. Endoplasmic reticulum protein BI-1 modulates unfolded protein
response signaling and protects against stroke and traumatic brain injury. Brain Res
1370: 227–237, 2011.
85. Kroemer G, Marino G, Levine B. Autophagy and the integrated stress response. Mol
Cell 40: 280 –293, 2010.
86. Ku SC, Lee J, Lau J, Gurumurthy M, Ng R, Lwa SH, Lee J, Klase Z, Kashanchi F, Chao
SH. XBP-1, a novel human T-lymphotropic virus type 1 (HTLV-1) tax binding protein,
activates HTLV-1 basal and tax-activated transcription. J Virol 82: 4343– 4353, 2008.
87. Ladiges WC, Knoblaugh SE, Morton JF, Korth MJ, Sopher BL, Baskin CR, MacAuley A,
Goodman AG, LeBoeuf RC, Katze MG. Pancreatic beta-cell failure and diabetes in
mice with a deletion mutation of the endoplasmic reticulum molecular chaperone
gene P58IPK. Diabetes 54: 1074 –1081, 2005.
88. Lee AH, Chu GC, Iwakoshi NN, Glimcher LH. XBP-1 is required for biogenesis of
cellular secretory machinery of exocrine glands. EMBO J 24: 4368 – 4380, 2005.
89. Lee AH, Scapa E, Cohen D, Glimcher L. Regulation of hepatic lipogenesis by the
transcription factor XBP1. Science 320: 1492, 2008.
90. Lee AH, Chu GC, Iwakoshi NN, Glimcher LH. XBP-1 is required for biogenesis of
cellular secretory machinery of exocrine glands. EMBO J 24: 4368 – 4380, 2005.
91. Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:
7448 –7459, 2003.
92. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K,
Kaufman RJ. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6
cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes
Dev 16: 452– 466, 2002.
93. Lee KP, Dey M, Neculai D, Cao C, Dever TE, Sicheri F. Structure of the dual enzyme
Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell
132: 89 –100, 2008.
94. Li H, Korennykh AV, Behrman SL, Walter P. Mammalian endoplasmic reticulum stress
sensor IRE1 signals by dynamic clustering. Proc Natl Acad Sci USA 107: 16113–16118,
2010.
95. Li J, Lee B, Lee AS. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA
by p53. J Biol Chem 281: 7260 –7270, 2006.
76. Kimata Y, Kimata YI, Shimizu Y, Abe H, Farcasanu IC, Takeuchi M, Rose MD, Kohno
K. Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell 14: 2559 –2569, 2003.
96. Liang G, Audas TE, Li Y, Cockram GP, Dean JD, Martyn AC, Kokame K, Lu R.
Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. Mol Cell Biol 26: 7999 –
8010, 2006.
77. Kimata Y, Oikawa D, Shimizu Y, Ishiwata-Kimata Y, Kohno K. A role for BiP as an
adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J Cell Biol 167:
445– 456, 2004.
97. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, Lavail MM,
Walter P. IRE1 signaling affects cell fate during the unfolded protein response. Science
318: 944 –949, 2007.
1240
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
63. Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH.
Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 4: 321–329, 2003.
78. Klee M, Pallauf K, Alcala S, Fleischer A, Pimentel-Muinos FX. Mitochondrial apoptosis
induced by BH3-only molecules in the exclusive presence of endoplasmic reticular
Bak. EMBO J 28: 1757–1768, 2009.
HETZ ET AL.
98. Lin JH, Li H, Zhang Y, Ron D, Walter P. Divergent effects of PERK and IRE1 signaling
on cell viability. PLoS One 4: e4170, 2009.
120. Minamino T, Kitakaze M. ER stress in cardiovascular disease. J Mol Cell Cardiol 48:
1105–1110, 2010.
99. Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases. Cell
Death Differ 13: 385–392, 2006.
121. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through
cellular self-digestion. Nature 451: 1069 –1075, 2008.
100. Lipson KL, Fonseca SG, Ishigaki S, Nguyen LX, Foss E, Bortell R, Rossini AA, Urano F.
Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulumresident protein kinase IRE1. Cell Metab 4: 245–254, 2006.
122. Moenner M, Pluquet O, Bouchecareilh M, Chevet E. Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67: 10631–10634, 2007.
101. Lipson KL, Fonseca SG, Urano F. Endoplasmic reticulum stress-induced apoptosis and
auto-immunity in diabetes. Curr Mol Med 6: 71–77, 2006.
102. Lipson KL, Ghosh R, Urano F. The role of IRE1alpha in the degradation of insulin
mRNA in pancreatic beta-cells. PLoS ONE 3: e1648, 2008.
103. Lisbona F, Hetz C. Turning off the unfolded protein response: an interplay between
the apoptosis machinery and ER stress signaling. Cell Cycle 8: 1643–1644, 2009.
104. Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F, Glavic A,
Kress C, Lin JH, Walter P, Reed JC, Glimcher LH, Hetz C. BAX inhibitor-1 is a negative
regulator of the ER stress sensor IRE1alpha. Mol Cell 33: 679 – 691, 2009.
106. Luo D, He Y, Zhang H, Yu L, Chen H, Xu Z, Tang S, Urano F, Min W. AIP1 is critical
in transducing IRE1-mediated endoplasmic reticulum stress response. J Biol Chem 283:
11905–11912, 2008.
107. Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4: 966 –977, 2004.
108. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk
between autophagy and apoptosis. Nat Rev Mol Cell Biol 8: 741–752, 2007.
109. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious
cycle or a double-edged sword? Antioxid Redox Signal 9: 2277–2293, 2007.
110. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding
HP, Ron D. CHOP induces death by promoting protein synthesis and oxidation in the
stressed endoplasmic reticulum. Genes Dev 18: 3066 –3077, 2004.
111. Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L. Heat shock
protein 90 modulates the unfolded protein response by stabilizing IRE1alpha. Mol Cell
Biol 22: 8506 – 8513, 2002.
112. Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor
XBP1 regulates innate immune responses in macrophages. Nature Immunol 11: 411–
418, 2010.
113. Matus S, Glimcher LH, Hetz C. Protein folding stress in neurodegenerative diseases:
a glimpse into the ER. Curr Opin Cell Biol 23: 239 –252, 2011.
114. Matus S, Lisbona F, Torres M, León C, Thielen P, Hetz C. The stress rheostat: an
interplay between the unfolded protein response (UPR) and autophagy in neurodegeneration. Curr Mol Med 8: 157–172, 2008.
115. Matus S, Nassif M, Glimcher LH, Hetz C. XBP-1 deficiency in the nervous system
reveals a homeostatic switch to activate autophagy. Autophagy 5: 1226 –1228, 2009.
116. Mauro C, Crescenzi E, De Mattia R, Pacifico F, Mellone S, Salzano S, de Luca C,
D’Adamio L, Palumbo G, Formisano S, Vito P, Leonardi A. Central role of the scaffold
protein tumor necrosis factor receptor-associated factor 2 in regulating endoplasmic
reticulum stress-induced apoptosis. J Biol Chem 281: 2631–2638, 2006.
117. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes
cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the
cellular redox state. Mol Cell Biol 21: 1249 –1259, 2001.
118. McGuckin MA, Eri RD, Das I, Lourie R, Florin TH. ER stress and the unfolded protein
response in intestinal inflammation. Am J Physiol Gastrointest Liver Physiol 298: G820 –
G832, 2010.
119. Meex SJR, van Greevenbroek MMJ, Ayoubi TA, Vlietinck R, van Vliet-Ostaptchouk JV,
Hofker MH, Vermeulen VMMJ, Schalkwijk CG, Feskens EJM, Boer JMA, Stehouwer
CDA, van der Kallen CJH, de Bruin TWA. Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2
diabetes in Dutch Caucasians. J Clin Endocrinol Metab 92: 2720 –2725, 2007.
124. Murakami T, Saito A, Hino S, Kondo S, Kanemoto S, Chihara K, Sekiya H, Tsumagari
K, Ochiai K, Yoshinaga K, Saitoh M, Nishimura R, Yoneda T, Kou I, Furuichi T, Ikegawa
S, Ikawa M, Okabe M, Wanaka A, Imaizumi K. Signalling mediated by the endoplasmic
reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol 11:
1205–1211, 2009.
125. Nagai A, Kadowaki H, Maruyama T, Takeda K, Nishitoh H, Ichijo H. USP14 inhibits
ER-associated degradation via interaction with IRE1alpha. Biochem Biophys Res Commun 379: 995–1000, 2009.
126. Naidoo N. ER and aging-Protein folding and the ER stress response. Ageing Res Rev 8:
150 –159, 2009.
127. Nassif M, Matus S, Castillo K, Hetz C. Amyotrophic lateral sclerosis pathogenesis: a
journey through the secretory pathway. Antioxid Redox Signal 13: 1955–1989, 2010.
128. Navon A, Gatushkin A, Zelcbuch L, Shteingart S, Farago M, Hadar R, Tirosh B. Direct
proteasome binding and subsequent degradation of unspliced XBP-1 prevent its intracellular aggregation. FEBS Lett 584: 67–73, 2010.
129. Nekrutenko A, He J. Functionality of unspliced XBP1 is required to explain evolution
of overlapping reading frames. Trends Genet 22: 645– 648, 2006.
130. Nguyen DT, Kebache S, Fazel A, Wong HN, Jenna S, Emadali A, Lee EH, Bergeron JJ,
Kaufman RJ, Larose L, Chevet E. Nck-dependent activation of extracellular signalregulated kinase-1 and regulation of cell survival during endoplasmic reticulum stress.
Mol Biol Cell 15: 4248 – 4260, 2004.
131. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H. ASK1 is essential for endoplasmic reticulum stress-induced neuronal
cell death triggered by expanded polyglutamine repeats. Genes Dev 16: 1345–1355,
2002.
132. Niwa M, Patil CK, DeRisi J, Walter P. Genome-scale approaches for discovering novel
nonconventional splicing substrates of the Ire1 nuclease. Genome Biol 6: R3, 2005.
133. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi
M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K. Autophagy
is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:
9220 –9231, 2006.
134. Oikawa D, Akai R, Iwawaki T. Positive contribution of the IRE1alpha-XBP1 pathway
to placental expression of CEA family genes. FEBS Lett 584: 1066 –1070, 2010.
135. Oikawa D, Kimata Y, Kohno K, Iwawaki T. Activation of mammalian IRE1alpha upon
ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins. Exp Cell Res 315: 2496 –2504, 2009.
136. Oikawa D, Tokuda M, Hosoda A, Iwawaki T. Identification of a consensus element
recognized and cleaved by IRE1 alpha. Nucleic Acids Res 38: 6265– 6273, 2010.
137. Oliver JD, Roderick HL, Llewellyn DH, High S. ERp57 functions as a subunit of specific
complexes formed with the ER lectins calreticulin and calnexin. Mol Biol Cell 10:
2573–2582, 1999.
138. Onn A, Ron D. Modeling the endoplasmic reticulum unfolded protein response. Nat
Struct Mol Biol 17: 924 –925, 2010.
139. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün
C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin
action, and type 2 diabetes. Science 306: 457– 461, 2004.
140. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, SolowCordero DE, Bouley DM, Offner F, Niwa M, Koong AC. Identification of an Ire1alpha
endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 117: 1311–1314, 2011.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1241
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
105. Liu CY, Schroder M, Kaufman RJ. Ligand-independent dimerization activates the
stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum. J
Biol Chem 275: 24881–24885, 2000.
123. Mori K, Kawahara T, Yoshida H, Yanagi H, Yura T. Signalling from endoplasmic
reticulum to nucleus: transcription factor with a basic-leucine zipper motif is required
for the unfolded protein-response pathway. Genes Cells 1: 803– 817, 1996.
THE UNFOLDED PROTEIN RESPONSE
141. Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U. The regulatory
subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear
translocation. Nature Med 16: 429 – 437, 2010.
142. Perlmutter DH. The cellular response to aggregated proteins associated with human
disease. J Clin Invest 110: 1219 –1220, 2002.
143. Pincus D, Chevalier MW, Aragon T, van Anken E, Vidal SE, El-Samad H, Walter P. BiP
binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded
protein response. PLoS Biol 8: e1000415, 2010.
144. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD,
Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P,
Strasser A. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:
1337–1349, 2007.
145. Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, Chen Y, Wu D, Xie D, Lin X, Gao X,
Kaufman RJ, Li W, Liu Y. A crucial role for RACK1 in the regulation of glucosestimulated IRE1alpha activation in pancreatic beta cells. Sci Signal 3: ra7, 2010.
147. Reimertz C, Kogel D, Rami A, Chittenden T, Prehn JH. Gene expression during ER
stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA
and activation of the mitochondrial apoptosis pathway. J Cell Biol 162: 587–597, 2003.
148. Reimold AM, Etkin A, Clauss I, Perkins A, Friend DS, Zhang J, Horton HF, Scott A,
Orkin SH, Byrne MC, Grusby MJ, Glimcher LH. An essential role in liver development
for transcription factor XBP-1. Genes Dev 14: 152–157, 2000.
149. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH. Plasma cell differentiation requires
the transcription factor XBP-1. Nature 412: 300 –307, 2001.
150. Ren D, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP,
Hsieh JJ, Cheng EH. BID, BIM, and PUMA are essential for activation of the BAX- and
BAK-dependent cell death program. Science 330: 1390 –1393, 2010.
162. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev
Biochem 74: 739 –789, 2005.
163. Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach-Faller N, RudnikSchöneborn S, Blaschek A, Wolf NI, Harting I, North K, Smith J, Muntoni F, Brockington M, Quijano-Roy S, Renault F, Herrmann R, Hendershot LM, Schröder JM,
Lochmüller H, Topaloglu H, Voit T, Weis J, Ebinger F, Zerres K. Mutations in SIL1
cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy.
Nature Genet 37: 1312–1314, 2005.
164. Shaffer AL, Shapiro-Shelef M, Iwakoshi NN, Lee AH, Qian SB, Zhao H, Yu X, Yang L,
Tan BK, Rosenwald A, Hurt EM, Petroulakis E, Sonenberg N, Yewdell JW, Calame K,
Glimcher LH, Staudt LM. XBP1, downstream of Blimp-1, expands the secretory
apparatus and other organelles, increases protein synthesis in plasma cell differentiation. Immunity 21: 81–93, 2004.
165. Shore GC, Papa FR, Oakes SA. Signaling cell death from the endoplasmic reticulum
stress response. Curr Opin Cell Biol 23: 143–149, 2011.
166. Sidrauski C, Walter P. The transmembrane kinase Ire1p is a site-specific endonuclease
that initiates mRNA splicing in the unfolded protein response. Cell 90: 1031–1039,
1997.
167. Silva RM, Ries V, Oo TF, Yarygina O, Jackson-Lewis V, Ryu EJ, Lu PD, Marciniak SJ,
Ron D, Przedborski S, Kholodilov N, Greene LA, Burke RE. CHOP/GADD153 is a
mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem 95: 974 –986, 2005.
168. Sriburi R, Bommiasamy H, Buldak GL, Robbins GR, Frank M, Jackowski S, Brewer JW.
Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis. J Biol Chem 282:
7024 –7034, 2007.
151. Richardson CE, Kooistra T, Kim DH. An essential role for XBP-1 in host protection
against immune activation in C. elegans. Nature 463: 1092–1095, 2010.
169. Sriburi R, Jackowski S, Mori K, Brewer JW. XBP1: a link between the unfolded protein
response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J Cell Biol
167: 35– 41, 2004.
152. Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene. Clin Genet 79:
103–117, 2011.
170. Stevens FJ, Argon Y. Protein folding in the ER. Semin Cell Dev Biol 10: 443– 454, 1999.
153. Rodriguez D, Rojas-Rivera D, Hetz C. Integrating stress signals at the endoplasmic
reticulum: the BCL-2 protein family rheostat. Biochim Biophys Acta 1813: 564 –574,
2010.
154. Romero-Ramirez L, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, Mori K,
Glimcher LH, Denko NC, Giaccia AJ, Le QT, Koong AC. XBP1 is essential for survival
under hypoxic conditions and is required for tumor growth. Cancer Res 64: 5943–
5947, 2004.
155. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein
response. Nat Rev Mol Cell Biol 8: 519 –529, 2007.
156. Rong J, Chen L, Toth JI, Tcherpakov M, Petroski MD, Reed JC. Bifunctional apoptosis
regulator (BAR), an endoplasmic reticulum (ER)-associated E3 ubiquitin ligase, modulates BI-1 protein stability and function in ER stress. J Biol Chem 286: 1453–1463,
2011.
157. Rubio C, Pincus D, Korennykh A, Schuck S, El-Samad H, Walter P. Homeostatic
adaptation to endoplasmic reticulum stress depends on Ire1 kinase activity. J Cell Biol
193: 171–184, 2011.
171. Stirling J, O’Hare P. CREB4, a transmembrane bZip transcription factor and potential
new substrate for regulation and cleavage by S1P. Mol Biol Cell 17: 413– 426, 2006.
172. Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox
NJ, Lipkind GM, Lipton RB, Greeley SAW, Patch AM, Ellard S, Steiner DF, Hattersley
AT, Philipson LH, Bell GI, Group NDIC. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 104: 15040 –15044, 2007.
173. Tabas I. The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ Res 107: 839 – 850, 2010.
174. Tam LS, Gu J, Yu D. Pathogenesis of ankylosing spondylitis. Nature Rev Rheumatol 6:
399 – 405, 2010.
175. Thameem F, Farook VS, Bogardus C, Prochazka M. Association of amino acid variants
in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes
in Pima Indians. Diabetes 55: 839 – 842, 2006.
176. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 8: 663– 674, 2008.
158. Rutkevich LA, Williams DB. Participation of lectin chaperones and thiol oxidoreductases in protein folding within the endoplasmic reticulum. Curr Opin Cell Biol 23:
157–166, 2010.
177. Todd DJ, McHeyzer-Williams LJ, Kowal C, Lee AH, Volpe BT, Diamond B,
McHeyzer-Williams MG, Glimcher LH. XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. J Exp
Med 206: 2151–2159, 2009.
159. Saito A, Hino S, Murakami T, Kanemoto S, Kondo S, Saitoh M, Nishimura R, Yoneda
T, Furuichi T, Ikegawa S, Ikawa M, Okabe M, Imaizumi K. Regulation of endoplasmic
reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for
chondrogenesis. Nat Cell Biol 11: 1197–1204, 2009.
178. Turner MJ, Delay ML, Bai S, Klenk E, Colbert RA. HLA-B27 up-regulation causes
accumulation of misfolded heavy chains and correlates with the magnitude of the
unfolded protein response in transgenic rats: Implications for the pathogenesis of
spondylarthritis-like disease. Arthritis Rheum 56: 215–223, 2007.
160. Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J. ER stress in Alzheimer’s
disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J Neuroinflammation 6: 41, 2009.
179. Uemura A, Oku M, Mori K, Yoshida H. Unconventional splicing of XBP1 mRNA
occurs in the cytoplasm during the mammalian unfolded protein response. J Cell Sci
122: 2877–2886, 2009.
1242
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
146. Rapoport TA. Protein translocation across the eukaryotic endoplasmic reticulum and
bacterial plasma membranes. Nature 450: 663– 669, 2007.
161. Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JWM, Tsukamoto K,
Ribick M, Schuit FC, Kaufman RJ. Control of mRNA translation preserves endoplasmic
reticulum function in beta cells and maintains glucose homeostasis. Nature Med 11:
757–764, 2005.
HETZ ET AL.
180. Urano F, Bertolotti A, Ron D. IRE1 and efferent signaling from the endoplasmic
reticulum. J Cell Sci 113: 3697–3702, 2000.
181. Vembar SS, Brodsky JL. One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9: 944 –957, 2008.
182. Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, Kriebel D, Der-Sarkissian
A, Krishnan K, Schweitzer C, Liu Z, Malyankar UM, Chiovitti D, Canny M, Durocher
D, Sicheri F, Patterson JB. Potent and selective inhibitors of the inositol-requiring
enzyme 1 endoribonuclease. J Biol Chem 286: 12743–12755, 2011.
183. Wang FM, Chen YJ, Ouyang HJ. Regulation of unfolded protein response modulator
XBP1s by acetylation and deacetylation. Biochem J 433: 245–252, 2010.
184. Wang L, Popko B, Roos RP. The unfolded protein response in familial amyotrophic
lateral sclerosis. Hum Mol Genet 20: 1008 –1015, 2011.
185. Wang Y, Inoue H, Ravnskjaer K, Viste K, Miller N, Liu Y, Hedrick S, Vera L, Montminy
M. Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity.
Proc Natl Acad Sci USA 107: 3087–3092, 2010.
187. Weiss MA. Proinsulin and the genetics of diabetes mellitus. J Biol Chem 284: 19159 –
19163, 2009.
188. Williams DB. Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum. J Cell Sci 119: 615– 623, 2006.
189. Winnay JN, Boucher J, Mori MA, Ueki K, Kahn CR. A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box-binding protein-1 to
modulate the unfolded protein response. Nat Med 16: 438 – 445, 2010.
190. Wiseman RL, Zhang Y, Lee KP, Harding HP, Haynes CM, Price J, Sicheri F, Ron D.
Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase
domain of IRE1. Mol Cell 38: 291–304, 2010.
191. Woehlbier U, Hetz C. Modulating stress responses by the UPRosome: a matter of life
and death. Trends Biochem Sci 10.1016/j.tibs.2011.03.0012011.
192. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K.
Transcriptional induction of mammalian ER quality control proteins is mediated by
single or combined action of ATF6alpha and XBP1. Dev Cell 13: 365–376, 2007.
197. Yoshida H, Oku M, Suzuki M, Mori K. pXBP1(U) encoded in XBP1 pre-mRNA
negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER
stress response. J Cell Biol 172: 565–575, 2006.
198. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell
death. Nat Rev Mol Cell Biol 9: 47–59, 2008.
199. Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH, Kaufman RJ.
Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124: 587–599, 2006.
200. Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H,
Leonardi R, Chen YE, Jackowski S, Kaufman RJ. The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J 30: 1357–
1375, 2011.
201. Zhang K, Wong HN, Song B, Miller CN, Scheuner D, Kaufman RJ. The unfolded
protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest 115: 268 –281, 2005.
202. Zhang P, Mcgrath B, Li Sa Frank A, Zambito F, Reinert J, Gannon M, Ma K, Mcnaughton K, Cavener DR. The PERK eukaryotic initiation factor 2 alpha kinase is
required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 22: 3864 –3874, 2002.
203. Zhao F, Edwards R, Dizon D, Afrasiabi K, Mastroianni JR, Geyfman M, Ouellette AJ,
Andersen B, Lipkin SM. Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2⫺/⫺ mice. Dev Biol 338: 270 –279,
2010.
204. Zhao L, Longo-Guess C, Harris BS, Lee JW, Ackerman SL. Protein accumulation and
neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a
cochaperone of BiP. Nature Genet 37: 974 –979, 2005.
205. Zhao L, Rosales C, Seburn K, Ron D, Ackerman SL. Alteration of the unfolded protein
response modifies neurodegeneration in a mouse model of Marinesco-Sjögren syndrome. Hum Mol Genet 19: 25–35, 2010.
193. Yanagitani K, Imagawa Y, Iwawaki T, Hosoda A, Saito M, Kimata Y, Kohno K. Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of
its own mRNA. Mol Cell 34: 191–200, 2009.
206. Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ. The crystal structure
of human IRE1 luminal domain reveals a conserved dimerization interface required for
activation of the unfolded protein response. Proc Natl Acad Sci USA 103: 14343–
14348, 2006.
194. Yanagitani K, Kimata Y, Kadokura H, Kohno K. Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science 331: 586 –589,
2011.
207. Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Fisher SJ, White MF, Biddinger SB,
Ozcan U. Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction. Nat
Med 17: 356 –365, 2011.
195. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by
ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107: 881– 891, 2001.
208. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL,
Ron D. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12: 982–995, 1998.
Physiol Rev • VOL 91 • OCTOBER 2011 • www.prv.org
1243
Downloaded from http://physrev.physiology.org/ by 10.220.33.5 on July 4, 2017
186. Wang Y, Vera L, Fischer WH, Montminy M. The CREB coactivator CRTC2 links
hepatic ER stress and fasting gluconeogenesis. Nature 460: 534 –537, 2009.
196. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, Mori K. ATF6 activated by
proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element
responsible for the mammalian unfolded protein response. Mol Cell Biol 20: 6755–
6767, 2000.