Physiol Rev 86: 1133–1149, 2006;
doi:10.1152/physrev.00015.2006.
Endoplasmic Reticulum Stress Signaling in Disease
STEFAN J. MARCINIAK AND DAVID RON
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; and
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York
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Marciniak, Stefan J., and David Ron. Endoplasmic Reticulum Stress Signaling in Disease. Physiol Rev 86:
1133–1149, 2006; doi:10.1152/physrev.00015.2006.—The extracellular space is an environment hostile to unmodified
polypeptides. For this reason, many eukaryotic proteins destined for exposure to this environment through secretion
or display at the cell surface require maturation steps within a specialized organelle, the endoplasmic reticulum
(ER). A complex homeostatic mechanism, known as the unfolded protein response (UPR), has evolved to link the
load of newly synthesized proteins with the capacity of the ER to mature them. It has become apparent that
dysfunction of the UPR plays an important role in some human diseases, especially those involving tissues dedicated
to extracellular protein synthesis. Diabetes mellitus is an example of such a disease, since the demands for
constantly varying levels of insulin synthesis make pancreatic ␤-cells dependent on efficient UPR signaling.
Furthermore, recent discoveries in this field indicate that the importance of the UPR in diabetes is not restricted to
the ␤-cell but is also involved in peripheral insulin resistance. This review addresses aspects of the UPR currently
understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.
I. INTRODUCTION
The success of multicellular organisms owes much to
the efficiency gained from the cooperation between specialized cell types. This cooperation requires communication between distant components frequently achieved by
the binding of molecules from one cell to receptors on
another. Such information transfer requires proteins to be
synthesized that can withstand the harsh extracellular
environment, both as soluble ligands (hormones and
transmitters) and cell surface molecules (receptors and
adhesion molecules).
The extracellular compartment differs sufficiently
from the cytosol that proteins destined for secretion or
insertion into the plasma membrane require modifications
inappropriate to the cytosol, such as glycosylation and
disulfide bond formation. Generation of these modifications necessitates a compartment topologically distinct
from the cytosol, which is provided by a membranous
network called the endoplasmic reticulum (ER). With
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evolution of this compartment, eukaryotes internalized a
portion of the extracellular space in which they modify,
fold, and assemble secreted and membrane proteins. The
evolution of eukaryotes also created the challenge of
regulating a protein maturation machinery outside the
confines of the cytosol. Failure of this machinery to fold
newly synthesized endoplasmic reticulum “client” proteins presents unique dangers to the cell and is termed
“ER stress.” Early in evolution, a homeostatic mechanism
developed to maintain the balance between the demand
for ER function and ER synthetic capacity; furthermore,
as organisms became more complex, especially with the
appearance of long-lived professional secretory cells, the
importance and complexity of this machinery increased
greatly.
This review addresses the mechanisms that enable
higher metazoans to produce extracellular proteins in the
face of varying demand and the consequences should
these mechanisms fail. In the first section, a brief overview of the ER protein maturation machinery is pre-
0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society
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I. Introduction
A. Synthesis, folding, and misfolding of ER protein
B. ER-associated degradation
C. The UPR
II. Endoplasmic Reticulum Homeostasis
A. Short-term perturbations
B. Long-term change
III. Concluding Remarks
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STEFAN J. MARCINIAK AND DAVID RON
sented, along with some of the consequences of protein
misfolding. Thereafter, the response to short-term perturbations in ER function is discussed, with emphasis given
to human diseases caused by dysregulation of this response, followed finally by an examination of the importance of ER stress signaling over the longer term to
secretory cell differentiation and lipid metabolism.
A. Synthesis, Folding, and Misfolding
of ER Protein
Physiol Rev • VOL
B. ER-Associated Degradation
Some proteins never attain their correct conformation, perhaps due to a mutation impeding correct folding
or because the cell lacks the energy to drive sufficient
cycles of chaperone interaction. After a lag period of
30 –90 min, misfolded ER client proteins are disposed of
by ER-associated degradation (ERAD) (107). The timer
that dictates this delay, at least for misfolded glycoproteins, is likely to be ER mannosidase I, which operates by
trimming mannose residues from N-linked glycans (38,
76). Evidence that this regulates degradation comes from
its inhibition, which retards ERAD (115, 186), and from its
overexpression, which enhances ERAD (72). Recently,
EDEM, a stress-inducible catalytically inactive mannosidase homolog, has been shown to interact with misfolded
glycoproteins and effect their extraction from the folding
cycle (43, 73, 122).
The path by which unfolded proteins are retrotranslocated into the cytosol is not clear. Some evidence supports a role for the original Sec61 translocon complex
(150, 228), although a new complex containing derlin-1
and p97, a cytosolic ATPase, has been shown to be involved in retrotranslocation of major histocompatibility
complex (MHC) class I molecules (106, 219). Once within
the cytosol, ERAD substrates are degraded by the ubiquitin/proteosome pathway (49, 51, 151).
For these synthetic and quality assurance processes
to proceed efficiently, there needs to be coordination
between the input load of unfolded client proteins and the
maturation machinery of the ER. If the client protein load
is excessive compared with the reserve of ER chaperones,
the cell is said to be experiencing “ER stress.” If unchecked, ER stress threatens to overwhelm the processing capacity of the ER, leading to the accumulation of
unfolded proteins and collapse of the secretory pathway.
Consequently, signaling pathways have evolved that respond to ER stress by regulating processes on both sides
of the ER membrane through an adaptive mechanism
termed the unfolded protein response (UPR).
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Translation of membrane and extracellular proteins
is performed by ribosomes on the cytosolic surface of the
ER (3, 94). A signal recognition particle within the cytosol
cotranslationally recognizes a signal sequence within the
nascent polypeptide chain and directs it to a proteinaceous pore in the ER membrane, the Sec61 complex (92,
127, 149).
Proteins achieve a specific folded conformation first
by acquisition of secondary structure, e.g., helices, due to
the intrinsic properties of the amino acid sequence (39).
This is followed by a further search for native structure,
which involves diffusion of these preformed segments
and assembly into larger modules (84). These processes
entail the burial of amino acid side chains into a closepacked structure excluding water from the protein’s core
(25). “Misfolding,” in this context, indicates that a protein
persistently maintains the potential for nonnative interactions that interfere with its structure and function. These
may involve normally buried residues being exposed to
the solvent promoting illegitimate interactions with other
cellular components. Another consequence of aberrant
folding is aggregation of proteins into insoluble higher
order structures. These may be of three varieties, all of
which may cause disease: disordered aggregates (e.g.,
rhodopsin in autosomal retinitis pigmentosa, Ref. 163),
amyloid fibrils (e.g., amyloid ␤-peptide/tau in Alzheimer’s
disease, Refs. 89, 148), and nonamyloid fibrils (e.g., ␣1antitryspin in ␣1-antitrypsin deficiency, Ref. 110).
Disordered aggregates are complex insoluble accumulations of protein resistant to normal degradation,
while both amyloid and nonamyloid fibrils are simple
noncovalent polymers, one-dimensional crystals formed
from repeating subunits. Nonamyloid fibrils are characteristic of the serpinopathies, human diseases caused by
mutations within the serpin family of proteins (111); these
mutations allow a specific intermolecular interaction resulting in polymerization. In contrast, amyloid can be
formed through polymerization of a number of otherwise
unrelated proteins, each causing a distinct disease (79,
148, 207). Despite intensive study of these aggregates,
surprisingly little is certain about the mechanism of their
toxicity; however, it is becoming apparent that even in the
case of amyloidoses, in which extracellular deposits are
characteristic, some of the deleterious effect comes from
toxic gain of function due to protein oligomers within the
cell (227).
The inappropriate interactions of misfolded proteins
threaten to disrupt normal cellular function, so the biosynthetic machinery has evolved sophisticated mechanisms to minimize their occurrence. Within the ER, chaperones such as BiP bind to incompletely folded proteins
shielding them from other molecules (13, 64, 65, 126, 200).
In addition, other catalysts directly promote correct folding by the addition of carbohydrates (63), cis-trans
isomerization about peptide bonds (166), and the creation
and rearrangement of disulfide bonds (189).
ENDOPLASMIC RETICULUM AND DISEASE
C. The UPR
II. ENDOPLASMIC RETICULUM HOMEOSTASIS
A. Short-Term Perturbations
Tissues whose primary function is the secretion of
protein should depend most strongly on the UPR, especially those liable to make large changes in ER client
protein load. A good example is the pancreatic ␤-cell,
which produces insulin in response to changes in circulating glucose. It constantly executes changes in ER synthetic capacity to track current glucose levels. Although
the precise mechanisms remain unclear, it has been esPhysiol Rev • VOL
tablished that upswings in glucose, at least in the short
term, promote proinsulin synthesis through enhanced
protein translation (75, 203). This stimulation of proinsulin translation by glucose is specific to the ␤-cell and
dependent on cis-acting elements in untranslated regions
of proinsulin mRNA (206). The resultant large fluctuations
in ER client protein load are compensated for by the UPR,
but render the ␤-cell highly vulnerable to defects in ER
stress signaling in animal models (54) and in human disease (34).
1. Regulating client protein load
Clues to the homeostatic importance of regulating
new protein synthesis in response to changes in ER load
have come from a rare human disease. Wolcott-Rallison
syndrome is an autosomal recessive condition characterized by early development of diabetes mellitus with associated bone, liver, renal, and neuronal defects (209). It has
been mapped to 2p12 where candidate gene analysis
yielded mutations in EIF2AK3 (34), better known as PKRlike eukaryotic initiation factor 2 (eIF2␣) kinase (PERK)
(56) or pancreatic eIF2␣ kinase (PEK) (171).
PERK is an ER-resident transmembrane protein ubiquitously expressed, but highly enriched in professional
secretory cells (56, 170, 171, 175). Its cytosolic portion is
highly homologous to a yeast stress-responsive kinase,
Gcn2p (56, 170). Unlike PERK, Gcn2p is a soluble protein
that enables yeast to adapt their rate of new protein
synthesis to the levels of available amino acids (125, 190,
191, 208). When amino acids are limiting, Gcn2p phosphorylates the ␣-subunit of eIF2␣.
The eIF2 complex is essential in all eukaryotes for
new protein synthesis, since it recruits the initiator methionyl tRNA to ribosomes about to begin translation (69).
Phosphorylation of eIF2␣ inhibits this activity and thus
globally reduces protein translation. In metazoans, the
GCN2 gene has expanded into a family of related eIF2␣
kinases, all of which inhibit protein translation in response to stress. These kinases all possess homologous
catalytic domains but have different stress-sensitive regulatory domains. GCN2 persists to respond to amino acid
starvation, while new members sense disparate stresses
including viral infection (PKR and PKZ) and iron deficiency (HRI) (9, 10, 23, 44, 159). The existence of PERK,
an ER transmembrane eIF2␣ kinase, led to the appreciation that cells are able to adjust their level of new protein
synthesis to match their ER folding capacity and prevent
overload of the secretory pathway (55, 56).
To respond to ER stress, PERK must transduce a
luminal signal across the ER membrane to its cytosolic
kinase domain. The nature of this stimulus is intriguing.
The ER is a site of secretory protein maturation and so
will, by necessity, harbor incompletely folded and actively
folding protein intermediates. The level of these is a reg-
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The nature of ER stress encountered by a cell dictates the nature of its UPR. During normal function a
secretory cell will experience dramatic variations in the
flux of new proteins through its ER in response to
changes in demand. During a transition from low protein
synthesis to high, there is a need to increase ER proteinfolding capacity to avoid overloading of chaperones. Consequently, the UPR regulates transcription factors whose
targets include genes for components of the ER protein
maturation machinery. However, inherent in this response is a temporal delay, since new chaperones cannot
be made instantly. To avoid the accumulation of misfolded client protein during this hiatus, the rate of secretory protein synthesis must also be under UPR-directed
modulation through a more rapid transcription-independent mechanism. Furthermore, when protein-folding efficiency falls, for instance, in ischemic tissue when lack of
energy impedes the proper function of ER chaperones
and enzymes, the primary adaptation may be through
reduced client synthesis rather than by increasing the
levels of this machinery, which itself would be costly in
energy. Therefore, both transcriptional and translational
signals emanate from the stressed ER to allow a coordinated response.
Not all changes in ER protein flux are transitory nor
can all perturbations be survived. In some cases the
change in ER protein synthesis accompanies a change in
cellular phenotype, such as during differentiation into a
secretory cell. Here the prolonged activation of UPR signaling itself appears to play a role in the differentiation
process, leading to dramatic alterations in ER structure.
When the level of ER stress is too great to allow adaptation, the cell may die. It remains unclear to what extent
the UPR plays a role directly in cell death, but studies of
ER stress lethality have revealed novel potential therapeutic targets for intervention in human disease.
These concepts will be elaborated upon in more detail below with emphasis on the human diseases to which
they are most relevant.
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Wolcott-Rallison patients, new proteins continue to enter
the ER regardless of its ability to fold them. This manifests as the accumulation of misfolded products (109) and
excessive stress signaling and culminates in cell death
(54). Interestingly, individual mutations of the other
known eIF2␣ kinases (PKR, HRI, and GCN2) do not result
in mice with diabetes, indicating that only eIF2␣ phosphorylation in response to ER stress is involved in this
phenotype (52, 217, 226).
The importance of translational regulation in response to ER stress may not be restricted to rare genetic
diseases, as a recent study, using transgenic mice subtly
impaired in their ability to phosphorylate eIF2␣ has revealed a phenotype remarkably similar to that of human
type II diabetes. PERK and all eIF2␣ kinases phosphorylate a single residue on their substrate: serine-51. Mutation of this serine to an alanine (eIF2␣S51A) prevents its
phosphorylation in response to any stress. Heterozygous
eIF2␣S51A mice are capable of significant translational
regulation by phosphorylation of the remaining population of eIF2␣ molecules and are born with normal pancreatic islets and under normal conditions do not develop
diabetes (164). In contrast, eIF2␣S51A homozygotes are
born with severe ␤-cell deficiency by late embryonic stage
(165). However, when heterozygous mice are fed a highfat diet, a new and interesting phenotype is revealed
(164). These mice are more prone to obesity because of a
failure to increase energy expenditure in response to the
excess calories. Remarkably, they more rapidly exhibit
hyperleptinemia, mild hyperinsulinemia, and raised fasting glucose, features of the “metabolic syndrome” currently dominating the epidemic of type 2 diabetes in developed countries. When islets from high-fat diet-fed
eIF2␣S51A mice were analyzed in vitro, they demonstrated
increased basal insulin secretion but reduced stimulated
insulin secretion. Prolonged high-fat feeding led to distension of the ER by unfolded proteins, including proinsulin,
and to profound glucose intolerance. This surprising finding highlights the exquisite sensitivity of pancreatic
␤-cells even to subtle dysregulation of eIF2a phosphorylation and raises the intriguing possibility that minor variations in efficiency of eIF2␣ phosphorylation could, in
principle, contribute to significant morbidity. As yet, no
studies have addressed the possible existence of such
variations in eIF2␣ signaling between patient groups, for
example, obese subjects with or without associated features of metabolic syndrome.
2. Integrated stress response
The effects of eIF2␣ phosphorylation are not restricted to attenuation of protein translation, but also
include activation of a transcriptional program. This is
illustrated in a family of white matter hypomyelination
disorders, termed CACH/VWM leukodystrophies. These
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ister of client protein throughput, rather than an indicator
of the ER’s capacity to fold them. A homeostatic mechanism that responded solely to unfolded protein could not,
therefore, measure the efficiency of ER protein biosynthesis, but, instead, only respond to the absolute client
load. Evolution appears to have found a more subtle
solution: PERK responds not to the level of misfolded
protein within the ER, but instead to changes in the ER
chaperone reserve, that is, to the unfolded/misfolded protein-to-chaperone ratio. BiP is an abundant chaperone
within the ER that binds to folding proteins through interaction with exposed hydrophobic residues. BiP overexpression has long been known to suppress the UPR (41,
197). Two potentially complementary models have been
proposed for the mechanism(s) involved. During unstressed conditions, BiP also binds to the luminal domain
of PERK (12, 108). This interaction correlates with the
inactive, monomeric state of PERK. When an increase in
ER client load is experienced, BiP dissociates from PERK,
perhaps through sequestration to unfolded clients or by
more direct mechanisms. The dissociation of the PERKBiP complex is hypothesized to allow PERK to cluster in
the plane of the membrane, leading to activation of the
cytosolic kinase domain through a process of trans-autophosphorylation and a dramatic increase in affinity towards eIF2␣ (12, 116).
Recently, crystal structure data on IRE1, whose luminal domain is homologous to that of PERK, raise the
possibility that direct binding of sensing molecules to
unfolded proteins might also take place (32). Dimerization of the luminal portion of IRE1 appears to generate a
groove similar to that found in the peptide-binding pocket
of MHC molecules. If the groove formed by dimerization
of IRE1 can be shown to bind unfolded proteins, this
would suggest an alternative model whereby unfolded
domains that are unbuffered by chaperones signal directly in the unfolded protein response, perhaps combining direct elements (unfolded protein) and indirect elements (chaperone reserve).
Humans with this Wolcott-Rallison syndrome share
some clinical features with PERK⫺/⫺ mice, which are
born with essentially normal islets that are capable of
normal insulin synthesis and secretion (54). Indeed, when
isolated islets from prediabetic PERK⫺/⫺ mice are challenged with glucose, their secretion of insulin is greater
than wild-type controls. During the first few weeks of life
these pups develop overt diabetes due to progressive
␤-cell destruction. These findings indicate that PERK is
essential for ␤-cells to cope with normal physiological ER
stress arising from day-to-day insulin synthesis. This involves restraining the insulin synthetic response to glucose by attenuating new protein translation. In other
words, protein synthesis is limited in normal animals by
eIF2␣ phosphorylation to a level with which the existing
ER machinery can cope; in the PERK⫺/⫺ animals and
ENDOPLASMIC RETICULUM AND DISEASE
FIG. 1. The integrated stress response (ISR). A: basally PERK is
maintained in an inactive state, perhaps through interactions with BiP,
while GTP-bound eIF2 complex efficiently supports new protein translation initiation. The guanine nucleotide exchange factor (GEF) eIF2B
maintains the GTP-bound population of eIF2 complexes. B: during endoplasmic reticulum (ER) stress BiP dissociates from PERK, which
becomes active. Unfolded protein might interact directly with the luminal domain of PERK to promote activation. Phosphorylation of eIF2 on
its ␣-subunit leads directly to inhibition of eIF2B activity. When GTPbound eIF2 levels are limiting, most protein translation is inhibited,
while translation of ATF4 is enhanced. ATF4 migrates to the nucleus to
transactive genes of the ISR.
Physiol Rev • VOL
have shown that, rather than affecting global translation
rates during stress, these mutations increase signaling via
a transcription factor known as ATF4 (82, 193).
Whilst the majority of RNA transcripts experience
decreased translation during periods of increased eIF2␣
phosphorylation, a small and still poorly defined subset is
translated more efficiently (53, 68, 121, 124). This paradoxical effect is due to the presence of multiple upstream
open reading frames (uORFs) 5⬘ to the coding sequence
initiation codon (1, 68, 112, 194). The best-characterized
example in mammals is the stress-inducible transcription
factor ATF4 (112, 194). This transcript has two uORFs,
the second overlapping out of frame with the true ATF
coding sequence. During resting unstressed conditions,
ribosomes scan along the mRNA translating uORF1 and
then recapacitate by rebinding eIF2/GTP/Met-tRNA ternary complex in time to translate inhibitory uORF2. During stress, limiting levels of eIF2 ternary complex lead to
a delay in recapacitation of these scanning ribosomes,
such that they fail to reinitiate at uORF2 but instead scan
to the ATF4 initiation codon. By then, a proportion have
reacquired ternary complex allowing translation of the
active transcription factor.
In yeast, the single eIF2␣ kinase Gcn2p regulates a
transcription program governing the response to amino
acid deprivation through induction of the transcription
factor GCN4, by a mechanism analogous to that of ATF4
(37, 68, 125). As the family of eIF2␣ kinases has diversified to respond to numerous stresses, so too has the
transcriptional program it regulates in metazoans. It continues to regulate genes essential for amino acid sufficiency, but now ATF4 also induces antioxidant genes and
genes of the ER protein maturation machinery (57). Because eIF2␣ phosphorylation triggers a final common
pathway in response to many stresses, this transcriptional
program in combination with protein translation modulation has been termed the integrated stress response (ISR)
(57) (Fig. 1).
Oxidative protein folding is inextricably linked to the
generation of reactive oxygen species (ROS), in large part
through the activity of ER oxidase 1 (ERO1), which generates much of the oxidizing potential of the organelle
(48, 152, 187, 188). Without ER stress-regulated activation
of ATF4, PERK⫺/⫺ ␤-cells, and those from Wolcott-Rallison patients, lack the prosurvival effects of the ISR with
its antioxidant expression program (54, 57). It is worth
remarking, therefore, that recent data indicate the oxidation of cysteines to form disulfide bonds leads directly to
the generation of ROS and cell death (58) and that ER
stress-dependent ERO1␣ induction promotes ER oxidation (117). Insulin, with its three disulfide bonds per molecule, might therefore be expected to impose a considerable ROS load on the cell. The finding that targeted deletion of a widely expressed ER-associated reductase,
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are autosomal recessive conditions with a spectrum of
severity from congenital to adult-onset disease, involving
the progressive loss of mental and motor faculties due to
deterioration of brain white matter. In all cases the causative mutations have been found within subunits of an
eIF2␣-interacting protein, eIF2B (46, 47, 100, 158). As part
of its normal active cycle, eIF2 undergoes rounds of GTP
binding, hydrolysis, and guanine nucleotide exchange.
Only in the GTP-bound state is eIF2 capable of bringing
methionyl tRNA to the ribosome. The guanine nucleotide
exchange factor (GEF) for eIF2 is, in fact, eIF2B; however, once phosphorylated, eIF2 binds avidly to its GEF
inhibiting further exchange (27). In this way, phosphorylation of a small pool of eIF2 can inhibit most GEF activity
(Fig. 1). The mutations that cause the CACH/VWM disorders appear to interfere with eIF2B GEF activity, but
recent studies with cells from patients with CACH/VWM
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Ncb5or, leads to a selective loss of ␤-cells, once more
underlines their sensitivity to redox stress (212).
3. Recovery of protein translation
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A) EIF2␣ PHOSPHATASES. The execution of an adaptive
gene expression program like the ISR can only be performed if the attenuation of protein translation accompanying eIF2␣ phosphorylation is reversed (29, 114, 131).
Indeed, persisting loss of protein synthetic activity would
compromise cell survival, regardless of a need for adaptation to stress. For these reasons, phosphatase activity
exists to relieve eIF2␣ phosphorylation, restoring normal
translation initiation activity.
Viral infection leads to eIF2␣ phosphorylation
through activation of PKR (10, 90). This is part of an
innate antiviral response antagonizing viral protein translation. Frequently, the relationships between infective
agents and host are characterized by the adaptations of
one party being countered by adaptations within the
other. For example, viruses have evolved proteins that
directly inhibit the activity of PKR (21, 153); however, in
the case of herpes simplex virus (HSV), viral protein
translation can be maintained despite continued PKR activity. This is achieved through enhanced dephosphorylation of eIF2␣ by a virally encoded protein, ICP34.5, which
binds to a host serine/threonine phosphatase, protein
phosphatase 1 (PP1), and directs its activity towards
eIF2␣ (61, 62).
It is now well appreciated that protein phosphatases,
including PP1, are represented within the genome by
relatively few genes and achieve their specificity through
the formation of complexes with regulatory subunits (28).
It was therefore gratifying when suppressor screens of ER
signaling revealed two mammalian genes, CReP and
GADD34, with striking homology to ICP34.5 (80, 131).
These proved to be responsible for reversing PERK-induced translational attenuation, as they too are regulatory
subunits of PP1 that specifically promote eIF2␣ dephosphorylation (29, 80, 131). CReP is constitutively expressed, while GADD34 is strongly induced during ER
stress. The induction of GADD34 in particular appears
central to the reversal of stress-induced translational attenuation (18, 87, 114, 131, 132).
B) ROLE OF CHOP. Activation of ER stress signaling has
been correlated with the induction of cell death in many
models of ER stress. The mechanisms by which this might
promote cell death remain unclear; however, CHOP, a
transcription factor downstream of the PERK-ATF4 axis,
was thought to be important to the process, since its
deletion ameliorates tissue damage during ER stress (20,
136, 137, 174, 229). The downstream mediators of this
effect remained unknown until recent work demonstrated
that some of the toxic effects of CHOP are the result of
GADD34 induction (117).
The CHOP dependence of ER stress toxicity is well
illustrated in a murine model of diabetes, the Akita
mouse. Mice, unlike humans, have two genes encoding
insulin (Ins1 and Ins2). These appear functionally redundant, as deleting both alleles of either gene has no effect
on glucose homeostasis (101). It is therefore remarkable
that a spontaneous mutation in the Ins2 gene (Akita)
leads to a severe diabetic phenotype inherited as a semidominant trait (196, 223).
Insulin is translated as a single proinsulin polypeptide that undergoes oxidation within the ER to form three
intramolecular disulfide bonds. After excision of a short
peptide from the prohormone, these three bonds hold the
remaining two insulin chains together. The Akita mutation converts a conserved cysteine to tyrosine preventing
formation of one of these bonds (196). This mutant insulin
is not secreted, but instead degraded (8, 196). Mice harboring the Akita mutation have apparently normal pancreatic islets at birth, but go on to develop diabetes in the
ensuing weeks due to selective ␤-cell loss in the absence
of inflammation. This was initially attributed to nonspecific effects (196); however, when this mutation was introduced into mice with a targeted deletion of the CHOP
gene, onset of diabetes was significantly delayed due to
the preservation of ␤-cell numbers (136).
As indicated above, CHOP is a transcription factor
highly induced during ER stress (197, 229). The protective
effect of CHOP deletion appears not restricted to the
Akita mouse, since it also affords protection against cytokine-induced ␤-cell death, in which nitric oxide triggers
ER stress by the depletion of ER calcium stores (20, 137),
nor is it restricted to the pancreas, as CHOP⫺/⫺ animals
are resistant to renal damage caused by the ER stressinducing toxin tunicamycin (229). CHOP deletion also
protects mice from dopaminergic neuron loss following
6-hydroxydopamine injection (174). This drug, which is
commonly used as a model for Parkinson’s disease since
it selectively kills dopaminergic neurons in vivo, causes
ER stress in dopaminergic neurons in tissue culture (71,
162).
One popular hypothesis held that CHOP, a metazoan
specific gene, evolved to promote the death of individual
cells in response to insurmountable levels of ER stress,
affording particular benefit to multicellular organisms
(135). In accordance with this, CHOP overexpression has
been shown to sensitize cells to the toxicity of ER stress
(118). Analysis, however, of the CHOP transcriptional
program failed to reveal an obvious connection to pathways that promote cell death. Instead, CHOP appears to
defend ongoing protein secretion, in part through induction of GADD34 (117). In this light, it appears that the
ER-stressed cell is challenged with balancing the need to
defend its chaperone reserve, by limiting secretory protein synthesis, against the need of both cell and organism
for ongoing ER synthetic function. According to this
ENDOPLASMIC RETICULUM AND DISEASE
specific fashion. In cell culture, CHOP overexpression
leads to ROS production (118), and CHOP-dependent
ERO1␣ induction appears responsible for increased oxidation in the stressed ER (117). This may be relevant to
tissues known to be sensitive to redox perturbation, such
as the pancreatic ␤-cell.
Perhaps there are circumstances experienced by
multicellular organisms during which the cost of worsening ER stress is compensated for by enhanced protein
secretion, at least in a subset of cells. Because osteoblasts
are replenishable secretory cells they may behave in this
fashion and, consistent with this, recent data suggest that
the bones of CHOP⫺/⫺ animals demonstrate defects due
to impaired osteoblast function (147). If the importance of
CHOP in the defense of protein secretion is a general
feature of replenishable secretory cells, it is tempting to
speculate that terminally differentiated effector cells of
the immune system might also behave thus. Challenging
CHOP⫺/⫺ and GADD34 mutant animals with infectious
agents could test this hypothesis.
An exciting prediction arising from these findings is
that careful titration of GADD34 inhibitors might be of
therapeutic benefit in diseases involving ER stress,
through the preservation of ER chaperone reserve. It is
encouraging, therefore, that a recent screen for small
molecules that protect cells from ER stress yielded a
compound that enhances eIF2␣ phosphorylation and, in
HSV-infected cells, appears to block eIF2␣ dephosphorylation by ICP34.5 (15). If compounds can be synthesized
that have specificity for GADD34 over CReP, there exists
the potential for selective effects on ER-stressed tissue,
perhaps limiting systemic toxicity.
4. NF-␬B and ER activity
FIG. 2. Failure of ER homeostasis. The ratio of client protein load
(gray spheres) to the availability of chaperones (red caps) varies depending on new protein translation rates. When levels of new protein
exceed the capacity of ER chaperones to bind them, aggregation ensues.
PERK promotes eIF2␣ phosphorylation and thus inhibits protein translation, which is represented by a rightward shift in this figure. GADD34
induction, through eIF2␣ dephosphorylation and disinhibition of eIF2B
GEF activity, promotes protein translation and a leftward shift with an
increased risk of client protein aggregation. CHOP⫺/⫺ and GADD34
mutant cells experience lower levels of new protein aggregation because
reduced new protein synthesis defends the reserve of ER chaperones.
Physiol Rev • VOL
A distinct antiviral response initiated by the accumulation of viral proteins in the ER has previously been
postulated (140, 141, 143). This followed from observations that virally encoded proteins could activate NF-␬B
signaling in a cell autonomous fashion (119, 144, 145).
This is in contrast to most canonical NF-␬B stimuli, e.g.,
tumor necrosis factor (TNF)-␣, which originate from outside the cell. This “ER overload response” (EOR), as it
was termed, appeared not to be specific for viral proteins,
since other membrane proteins, e.g., MHC class I, when
overexpressed could also induce NF-␬B signaling (145). It
was subsequently extended to include NF-␬B induction
from ER accumulation of other nontransmembrane proteins, including ␣1-antitrypsin polymers (67, 95). The
transduction mechanism for this pathway remained obscure, although release of ER calcium and ROS were both
suggested (140, 143).
Recent discoveries have implicated PERK signaling
in the activation of NF-␬B in response to ER perturbations, challenging the notion that the EOR is distinct from
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model, the protection from death afforded by deletion of
the CHOP gene in some models of ER stress reflects,
therefore, an enforced shift of this balance from synthetic
function towards the defense of chaperone reserve (Fig.
2). In accordance with this, GADD34 null animals have
been shown to be protected from ER stress-induced nephrotoxicity equally well as CHOP⫺/⫺ animals (117).
Of course, there exists the formal possibility that
CHOP-dependent GADD34 induction evolved to promote
cell death rather than ongoing protein synthesis; however,
two pieces of evidence argue against this. First of all, in
tissue culture GADD34 mutant cells are more prone to
cell death in response to ER stress induced by thapsigargin (132). This agent causes ER stress through depletion
of ER calcium stores and is particularly effective at shutting down protein synthesis, indicating that recovery of
protein translation is necessary for the adaptive prosurvival effects of UPR signaling. Second, in murine models
of Pelizaeus-Merzbacher leukodystrophy (due to a proteolipid protein mutation), CHOP expression appears to
have an antiapoptotic effect, a strange phenotype for a
prodeath signal (176).
It remains unclear whether the toxic effects of CHOP
in models of ER stress are primarily mediated through
GADD34. Although this may be true for tunicamycininduced nephrotoxicity, it has yet to be proven for other
models. For example, it is possible that other CHOP target
genes, such as ERO1␣, may mediate toxicity in a tissue-
1139
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STEFAN J. MARCINIAK AND DAVID RON
B. Long-Term Change
In contrast to the continuous modulation of ER synthetic activity, differentiation of a cell into a highly secrePhysiol Rev • VOL
tory phenotype requires a dramatic expansion of ER. This
is exemplified in the development of B-lymphocytes into
plasma cells. In this regard, defects in plasma cell differentiation have helped reveal an additional role for the
UPR in the regulation of absolute ER mass within the cell.
1. Linking ER mass to demand
Multiple myeloma is a hematological neoplasm characterized by presence in the blood of a monoclonal immunoglobin or Bence Jones protein (free monoclonal ␬or ␭-light chains). These are produced by myeloma cells
within the bone marrow, which over time expand to
displace normal marrow leading to anemia and immunological deficiency. The plasma concentration of the monoclonal paraprotein can reach exceeding high levels (⬎100
g/l), even leading to complications through increased
blood viscosity. The causative myeloma cells are monoclonal expansions of plasma cells, immune cells normally
charged with large-scale immunoglobin manufacture.
To understand the genesis of plasma cells and myelomas, the transcription factors necessary for their differentiation have been determined. Early work demonstrated that myeloma cell lines frequently express a basic
leucine zipper transcription factor, XBP-1, to extremely
high levels (26, 204). XBP-1 was also shown to be essential for normal plasma cell differentiation (156, 157, 204).
Myeloma cells and mature plasma cells share the ability to
secrete huge quantities of immunoglobin, thanks to their
highly developed secretory pathway. Histologically these
cells have characteristically basophilic cytoplasm due to
the large numbers of ribosomes associated with their
extensive ER (Fig. 3). It seems likely that XBP-1’s role in
plasma cell differentiation is related to regulation of ER
expansion in response to increased demand (96). Furthermore, new therapeutic agents being developed to treat
myeloma may exploit the dependence of this neoplasm on
UPR activation (2, 66). Proteosome inhibitors have
proven to be highly effective in the killing of myeloma
cells and in early trials have achieved remarkable clinical
remissions in otherwise drug-resistant disease (81). Their
selectivity toward myelomas might reflect the reliance of
these cells on efficient ERAD, which itself is dependent
on XBP-1 signaling (96, 221). The first drug of this class,
bortezomib (Velcade), has now been approved by the
FDA for use in otherwise refractory disease (17).
XBP-1 regulates many genes of the unfolded protein
response in metazoans, including genes involved in generation of the ER membrane (177). It is upregulated at the
protein level during ER stress by a remarkable mechanism. The XBP-1 primary transcript is translated, albeit
inefficiently, to produce a protein without significant
transactivation activity (99). ER stress-dependent splicing
of XBP-1 mRNA involves excision of a short intron (26nt
in mammals) causing a frame shift in its open reading
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the UPR (36, 78). There exists a protein family of NF-␬B
inhibitors termed I-␬B, which, in unstimulated cells, is
expressed constitutively and sequesters NF-␬B inactive
within the cytoplasm (160). Classically, NF-␬B is activated through the relief of this inhibition, for example,
TNF receptor activation triggers I-␬B phosphorylation,
causing its ubiquitination and degradation by the proteosome (146). In the case of ER stress, at least when signaled by PERK, disinhibition of NF-␬B is achieved once
again by reducing I␬B levels, but through a novel mechanism. I-␬B has a far shorter half-life than NF-␬B. Consequently, translational attenuation preferentially lowers
I␬B levels, releasing NF-␬B to execute its transcription
program. A similar effect can be obtained by treatment of
cells in culture with other agents that inhibit protein
synthesis, e.g., cycloheximide (36, 78). This novel mechanism extends to NF-␬B activation in response to other
stresses, including ultraviolet (UV) irradiation and amino
acid deprivation, where GCN2 appears to be the relevant
kinase (77, 78, 211). Some controversy persists within this
field, since the existence of a PERK-dependent NF-␬B
cascade does not preclude activation of NF-␬B by other
ER-originating signals. This will be clarified once EOR
stressors have been more extensively studied in PERK
mutant and eIF2␣S51A cell lines.
The physiological significance of ER stress-induced
NF-␬B signaling likely reflects the importance of NF-␬B
signaling in other settings, namely, the coordination of inflammatory response and promotion of cellular survival. In
bacterial infection, the induction of NF-␬B by microbial
components sensed by Toll-like receptors leads to upregulation of early effectors of the innate immune response,
including chemokines, proinflammatory cytokines, and immune receptors (7, 91, 215). These early effectors then generate a further cycle of NF-␬B induction and generation of
an antimicrobial response (104). The induction of such a
cascade by detection of viral components within the ER, and
subsequent PERK-dependent NF-␬B activation, might represent an analogous antiviral response.
Developmentally, NF-␬B is a prosurvival signal in
some cell types, for example, in the maturation of B and
T lymphocytes and in the development and regeneration
of the liver (6, 103, 183, 210). While many stimuli that
induce NF-␬B also promote cell death, paradoxically
NF-␬B tends to oppose signal-induced cell death by induction of antiapoptotic genes including c-IAP1, c-IAP2,
and FLIP (120, 195). Indeed, NF-␬B can have proliferative
effects through its targets c-myc and cylcinD1 (142, 155).
It is therefore possible that NF-␬B induction may also link
secretory activity to trophic signals.
ENDOPLASMIC RETICULUM AND DISEASE
1141
2. Insulin resistance and ER stress
FIG. 3. The unfolded protein response (UPR). A: photomicrograph
(⫻1,000) of neoplastic plasma cells stained with eosin and hematoxylin
from a bone marrow aspirate in a case of multiple myeloma. Note the
lateral displacement of the nucleus by the extensive basophilic ER.
Scale bar is 10 ␮m. (Image kindly provided by Dr. Wendy Erber, Addenbrookes Hospital, UK.) B: ER stress causes signaling through three
distinct mediator proteins in the ER membrane offering redundancy
and, perhaps, a means to adjust the UPR to fit the circumstances of the
stress. Activated PERK phosphorylates eIF2␣ and inhibits new protein
translation. Additionally, ATF4 induction activates genes of the ISR,
including GADD34, which relieves translational attenuation, and
ERO1␣, which promotes oxidataive protein folding. Antioxidant targets
of ATF4 act to buffer increased reactive oxygen species (ROS) produced
by ERO1␣. ATF6 cleavage releases soluble ATF6c allowing transactivation of UPR target genes that increase the ER protein maturation machinery. IRE1-mediated activation of XBP1, which is more sustained due
to XBP1 autoinduction, leads to induction of genes involved both in the
maturation of ER client proteins and also genes that promote ER associated protein degradation.
frame, which introduces a new COOH-terminal transactivation domain to generate the active transcription factor
(19, 99, 169, 222). The endonuclease responsible for removing the inhibitory intron is an ER transmembrane
protein, IRE1, whose luminal domain shares significant
homology with that of PERK, allowing it a similar regulatory interaction with BiP (11, 12, 86, 108, 134). As with
PERK, ER stress-induced dissociation of BiP allows clustering of IRE1 and its activation through transautophosphorylation. In mammals there are, in fact, two IRE1
isoforms. IRE1␣ is detectable in all tissues (185), while
Physiol Rev • VOL
In addition to linking secretory capacity to demand
through regulation of ER expansion, IRE1 also plays an
important role in integrating ER stress signaling with
other stress and growth factor sensitive pathways.
An important feature of type 2 diabetes is peripheral
insulin resistance. Normally, activated insulin receptors
phosphorylate proximal signaling molecules, such as insulin receptor substrate 1 (IRS-1), on tyrosine residues,
which transduce the effects of insulin through interaction
with cytosolic targets (180, 182). In obesity (genetic or
dietary), this tyrosine phosphorylation is inhibited by
JNK-dependent serine phosphorylation of IRS-1 (4, 5).
Surprisingly, the mechanism of obesity-related JNK activation appears to involve ER stress.
For unclear reasons, liver and adipose cells from
obese mice show biochemical evidence of ER stress with
PERK activation, eIF2␣ phosphorylation, and BiP induction (139). It has previously been shown that ER stress,
through IRE1 activation, can directly trigger the JNK cascade (192). Activated IRE1 recruits the scaffolding protein TRAF2 to the ER membrane (192), which triggers a
mitogen-activated protein (MAP) kinase cascade leading
to JNK activation (129, 130). Thus IRE1 offers a plausible
mechanistic link between obesity and peripheral insulin
resistance. In this model, obesity-associated ER stress
would contribute to insulin resistance by causing JNK
activation through IRE1/TRAF2 with subsequent IRS-1
serine phosphorylation (Fig. 4). Consistent with this hypothesis, IRE1⫺/⫺ cells fail to active JNK or phosphorylate IRS-1 during ER stress unlike wild-type controls.
Supporting a causal link between peripheral ER stress
and insulin resistance, a recent study has demonstrated
protection against obesity-induced type 2 diabetes in mice
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IRE1␤ appears limited to the gut epithelium (198). The
significance of this tissue-dependent isoform expression
is unclear but may point toward cell type specific differences in UPR signaling. IRE1␣⫺/⫺ animals are not viable,
whereas IRE1␤ mutants appear well, although are more
prone to chemical-induced colitis (11, 185, 192).
The IRE1-dependent arm of the UPR is the most
ancient in evolutionary terms, since the entire UPR of
lower eukaryotes, including that of yeast, is regulated by
this molecule (30, 31, 40, 184, 185). Although in yeast the
target transcription factor HAC1 bares little homology to
XBP1, the activation of Ire1p is identical. It was, in fact,
historically the first UPR pathway to be described in
molecular terms (14, 22, 50, 85, 123, 167, 173, 202). In
yeast, after Ire1p-mediated intron excision from the
HAC1 mRNA, religation by the tRNA ligase Rlg1p generates an efficiently translated message (123, 161, 172). The
analogous ligase in higher organisms has yet to be identified and remains an important unanswered question.
1142
STEFAN J. MARCINIAK AND DAVID RON
3. ER stress and lipid metabolism
FIG. 4. Insulin resistance in obesity mediated by ER stress. A: in
nonobese subjects, glucose homeostasis is maintained by effectors of
insulin signaling. Insulin binding to its receptor causes tyrosine phosphorylation of IRS1, which in turn promotes activation of effector
proteins. B: in obesity, ER stress causes insulin resistance. IRE1 activation may then recruit TRAF2 to the ER membrane causing activation of
JNK, which in turn would promote phosphorylation of serine residues in
IRS1. Serine phosphorylation of IRS1 inhibits its tyrosine phosphorylation by activated insulin receptors, thus impairing insulin signaling.
by overexpression of an ER chaperone, while knockdown
of the same chaperone was diabetogenic (128). Furthermore, in the Akita mouse, systemic rather than ␤-cell
overexpression of an ER chaperone appeared to improve
peripheral insulin sensitivity (138).
In light of this, it is possible that the peripheral
insulin resistance seen in the eIF2␣S51A heterozygous
mice (above) might have resulted from increased signaling through the IRE1-JNK arm of the UPR attempting to
compensate for impaired PERK-dependent signaling.
Consistent with this speculation, PERK⫺/⫺ cells, which
are impaired in eIF2␣ phosphorylation, experience basally higher IRE1 activation (55).
Physiol Rev • VOL
A) HOMOCYSTEINE AND ATHEROSCLEROSIS. Among the
known risk factors for atherosclerosis, ER stress would
currently be ranked low, if at all. This may begin to
change as evidence accumulates implicating the UPR in
disordered lipid metabolism. The relationship between
the UPR and lipid accumulation is a complex one. On the
one hand, many target genes of the UPR involve lipid
synthesis, in part to allow expansion of the ER itself; on
the other hand, there is increasing evidence that perturbation of the lipid environment within the ER can activate
UPR signaling.
Homocysteinemia is associated with the development of atherosclerosis, certainly in patients with rare
inherited disorders of amino acid metabolism, but also in
the wider population, as indicated by large epidemiological studies (42, 70, 201). Although homocysteine is a
sulfur-containing amino acid, some of its toxic effects
appear to involve dysregulation of cholesterol and triglyceride biosynthesis (205). Patients with inherited hyperhomocysteinemia or laboratory animals fed a homocysteinerich diet develop hepatic steatosis in the absence of
marked rises in plasma lipids. The likely explanation is
local lipid synthesis, and consistent with this, homocysteine has been shown to activate lipogenic signaling via
the sterol regulated element-binding proteins (SREBPs)
(205). Surprisingly, ER stress contributes to the activation
of SREBP by homocysteine. Livers of homocysteine-fed
mice contain raised levels of ER chaperones, as do cultured cells exposed to high levels of homocysteine in
vitro. The importance of ER stress in this lipogenic signaling was demonstrated by BiP overexpression, which
ameliorated SREBP induction in response to homocysteine.
The relationship between the UPR and SREBP, while
clearly evident, is still not entirely explained in mechanis-
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It can be seen that the role of UPR signaling in
diabetes is far from straightforward. At the level of the
pancreatic ␤-cell, the UPR protects against developing
type I diabetes by ensuring that this highly secretory
tissue maintains efficient function despite wide swings in
ER protein flux. Conversely, chronic ER stress signaling
(perhaps related to obesity) appears involved in the etiology of peripheral insulin resistance. We can at present
only speculate as to how the UPR progresses from regulation to dysregulation over the passing years. It is known
that chronic exposure to elevated saturated free fatty
acids induces ER stress (83). Consequently, obesity-related ER stress may reflect the evolutionarily recent phenomenon of chronic nutrient excess. The dysregulation of
ER stress signaling seen in this disease may reflect the
lack of selection pressure to adapt this homeostatic mechanism to chronic inappropriate activation.
ENDOPLASMIC RETICULUM AND DISEASE
Physiol Rev • VOL
that have taken up oxidized lipoprotein particles and
become laden with cholesterol. This cholesterol is stored
as esters within large lipid vesicles, which give foam cells
their foamy appearance. Over time, death of these cells,
likely due to the toxic effects of unesterified cholesterol,
results in deposition of extracellular cholesterol within
the plaque. Unlike its esters, free cholesterol efficiently
inserts into lipid bilayers and can alter membrane physical properties. The ER membrane, being poor in free
cholesterol (16), may be especially sensitive to cholesterol loading. Indeed, recent findings indicate that for free
cholesterol to have its toxic effect it must be trafficked to
the ER (45). This trafficking results in activation of UPR
signaling and caspase activation, and eventually in macrophage apoptosis. In addition, ER stress caused by free
cholesterol loading of macrophages promotes chemokine
secretion, and this may contribute to the formation of
“vulnerable” atherosclerotic lesion, which are prone to
rupture as a function of their high inflammatory cell infiltrate (105).
III. CONCLUDING REMARKS
The complexity of the mammalian UPR, mediated as
it is by three distinct classes of ER sensors and numerous
transcription factors, may provide a degree of redundancy; however, perhaps a more interesting interpretation of this complexity may be to allow higher organisms
a more subtle response to ER stress. For example, the
division of UPR genes between multiple transcription
factors likely enables portions of the gene expression
program to be induced as is appropriate either to the
duration or intensity of ER stress. While ATF6 and XBP-1
transactivate many of the same genes, their expression
programs show important differences (97). Binding of
ATF6 to the BiP promoter is sufficient for maximal transactivation, while XBP-I binding is sufficient for maximal
induction of EDEM (97, 221). In contrast, many genes
require both arms to be active in order for best induction
(214). It has been suggested that an early, ATF6-dominated, response may attempt to compensate for ER stress
through chaperone induction alone. While XBP-1 activation, which is more sustained, may, in addition, promote
protein degradation through the induction of ERAD components. Accordingly, IRE1␣⫺/⫺ cells have been shown
defective in glycoprotein ERAD (221).
Repeatedly, models of ER dysfunction have generated models of diabetes, and investigations into rare genetic diabetic syndromes have revealed unexpected links
to ER stress. The field remains fertile for further study,
since mutations in ER stress-inducible genes such as
WFS1 (Wolfram syndrome) (74, 179, 181) and P58IPK
(93), which lead to diabetic syndromes, have yet to be
fully understood. Furthermore, the study of apparently
unrelated disease states including atherosclerosis, viral
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tic terms. The SREBPs are transmembrane proteins that,
under sterol-sufficient conditions, are retained within the
ER through interaction with other ER membrane proteins, Insig-1 and Insig-2 (213, 216). When cholesterol
levels are low, this interaction is weakened, whereupon
SREBP progresses to the Golgi to be cleaved sequentially
by two serine proteases, S1P and S2P (33). This cleavage
liberates the cytosolic portion of SREBP as a soluble
protein, which enters the nucleus to bind specific DNA
elements, thus transactivating target genes involved in
lipid synthesis. One possible mechanism of ER stressinduced SREBP activation, for which there is evidence,
involves stress-dependent loss of Insig-1 from the ER (98).
B) SREBP AND ATF6. Interestingly, the third known class
of ER stress sensor, exemplified by ATF6, is unrelated to
PERK or IRE1. ATF6 is another ER transmembrane protein, that undergoes processing similar to SREBP (24, 60,
102). It is normally retained within the ER through interaction, not with Insig proteins, but with BiP (168). During
ER stress, ATF6 is released from the ER and moves on to
the Golgi. There it is processed by the very same proteases that act on SREBP, to liberate a soluble transcription factor (218). Unlike SREBP, the targets of ATF6 are
classical UPR genes (133, 199, 220). Indeed, ATF6 was
isolated in a search for ligands of an ER stress responsive
DNA element (ESRE). Despite their separate transcriptional programs, there may still be some cross-talk between ATF6 and SREBP. A recent report suggests that
within the nucleus, cleaved ATF6 can bind SREBP2 directly to inhibit its transactivation potential and oppose
lipogenesis (224).
Following from the identification of ATF6, there have
been several related transcription factors identified,
which share similar domain structures and localization to
the ER [Luman (35, 113, 154), OASIS (88), CREBH (225),
ATF6b (59), CREB4 (178)]. The existence of such a variety of UPR signaling molecules at first seems puzzling, but
a clue to their roles may come from tissue distribution. In
the cases of OASIS and CREBH, at least, there is clear
evidence for tissue specificity, OASIS being found in astrocytes of the central nervous system, while CREBH is
restricted to the liver. This raises the possibility that ER
stress may elicit tissue-specific transcriptional responses.
In the case of CREBH for example, it has already been
shown that its activation by ER stress leads to induction
of genes of the acute phase response, providing a direct
link between hepatic ER stress and systemic inflammation (225).
C) CHOLESTEROL’S IMPACT ON THE ER. The dependence of
cholesterol metabolism on ER stress signaling may reflect
the impact of sterols on ER function. This is well illustrated by the macrophage in development of atherosclerosis. During the initial phase of atherosclerotic lesion
formation, foam cells are a characteristic histological
finding within the vessel intima. These are macrophages
1143
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STEFAN J. MARCINIAK AND DAVID RON
infection, and multiple myeloma may also benefit from
our increasing understanding of ER stress in their pathophysiology.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
S. J. Marciniak, Cambridge Institute for Medical Research, Univ.
of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK (e-mail: [email protected]); and D. Ron,
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016 (e-mail:
[email protected]).
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