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Endoplasmic Reticulum Stress
Responses in Plants
Stephen H. Howell
Plant Sciences Institute and Department of Genetics, Development, and Cell Biology, Iowa
State University, Ames, Iowa 50011; email: [email protected]
Annu. Rev. Plant Biol. 2013. 64:477–99
Keywords
First published online as a Review in Advance on
January 7, 2013
unfolded protein response, membrane-associated transcription factors,
IRE1, ERAD, autophagy, cell death
The Annual Review of Plant Biology is online at
plant.annualreviews.org
This article’s doi:
10.1146/annurev-arplant-050312-120053
c 2013 by Annual Reviews.
Copyright All rights reserved
Abstract
Endoplasmic reticulum (ER) stress is of considerable interest to plant
biologists because it occurs in plants subjected to adverse environmental
conditions. ER stress responses mitigate the damage caused by stress and
confer levels of stress tolerance to plants. ER stress is activated by misfolded proteins that accumulate in the ER under adverse environmental
conditions. Under these conditions, the demand for protein folding exceeds the capacity of the system, which sets off the unfolded protein
response (UPR). Two arms of the UPR signaling pathway have been
described in plants: one that involves two ER membrane–associated
transcription factors (bZIP17 and bZIP28) and another that involves
a dual protein kinase (RNA-splicing factor IRE1) and its target RNA
(bZIP60). Under mild or short-term stress conditions, signaling from
IRE1 activates autophagy, a cell survival response. But under severe or
chronic stress conditions, ER stress can lead to cell death.
477
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Contents
INTRODUCTION . . . . . . . . . . . . . . . . . .
MEMBRANE-ASSOCIATED
TRANSCRIPTION FACTORS . . .
bZIP17 and bZIP28 . . . . . . . . . . . . . . . .
Upregulation of Stress-Response
Genes . . . . . . . . . . . . . . . . . . . . . . . . . .
IRE1 AND THE RNA-SPLICING
ARM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
bZIP60 mRNA Splicing . . . . . . . . . . . .
Converging Pathways . . . . . . . . . . . . . .
PROTEIN FOLDING AND
N-LINKED
GLYCOSYLATION . . . . . . . . . . . . . .
ER-ASSOCIATED
DEGRADATION . . . . . . . . . . . . . . . . .
ER STRESS AND AUTOPHAGY . . . .
ER STRESS AND CELL DEATH . . .
Cell Sparing or Cell Death? . . . . . . . .
Difference Between Plants
and Animals . . . . . . . . . . . . . . . . . . . .
Endoplasmic
reticulum (ER): a
large membranous
organelle involved in
the production and
export of secreted
proteins
ER quality control
(ERQC): a system in
the ER that monitors
proteins for proper
folding and selects
misfolded proteins for
ERAD
ER-associated
degradation (ERAD):
a system in the ER
that degrades
misfolded proteins
ER stress: stress
produced by the
accumulation of
misfolded proteins in
the ER
478
478
479
480
481
482
482
483
484
486
489
490
491
492
INTRODUCTION
Protein folding has been one of the most
intensely studied processes in biology. Unlike protein synthesis, which is instructed by
DNA and RNA, protein folding is a selfassembly process, guided by entropic and energetic forces. The folding of large proteins in
particular can be finicky: There are many hills
and valleys in the energy landscape of protein
folding, and proteins can end up in nonnative
conformations (7, 28). Because protein folding
can be easily perturbed, it is a means by which
plants can perceive and respond to adverse environmental conditions (64).
Protein folding is an issue for secreted proteins because during synthesis they enter the
endoplasmic reticulum (ER) lumen as unfolded
polypeptides. Their folding is aided by factors
in the ER, and those proteins that do not fold
properly are detected by an ER quality control (ERQC) system and degraded by an ERassociated degradation (ERAD) system. ERQC
Howell
is important because misfolded proteins can be
deleterious to plant health. Even under the best
conditions, some proteins are misfolded. Under adverse environmental conditions or conditions of heavy protein secretion, however, the
demands for protein folding can exceed the capacity of the protein-folding and degradation
systems—leading to an increase in the load of
misfolded or unfolded protein in the ER, a condition that causes ER stress in plants (112).
ER stress sets off the unfolded protein
response (UPR). The UPR is a homeostatic
response to lighten the load of unfolded proteins in the ER by bringing the protein-folding
and degradation capacity of the ER into
alignment with the demand. The UPR has
been recognized in plants for a number of years
by its molecular signature (5, 14, 15): the upregulation of genes involved in protein folding
and ERAD (49, 75). ER stress also promotes
autophagy, and intense or prolonged ER stress
can lead to cell death, as discussed below.
The UPR can be induced in the laboratory
by treating plants with ER stress agents—
agents that interfere with protein folding in the
ER (89). One such agent is tunicamycin, which
interferes with N-linked glycosylation of secreted glycoproteins. N-glycans are recognized
at various steps in the protein-folding process,
and without N-linked glycosylation, folding is
interrupted and unfolded proteins accumulate.
Reducing agents, such as dithiothreitol, are also
ER stress agents because the proper folding of
proteins containing disulfide bonds requires an
oxidizing environment. In addition, inhibitors
of the ER calcium pump, such as cyclopiazonic
acid, serve as ER stress agents because the
major components of the ER protein-folding
apparatus, calnexin and calreticulin, are calcium dependent (79). Of course, ER stress
agents are proxies for the natural conditions
that elicit ER stress in plants. The UPR can be
induced by a variety of abiotic stresses, such as
heat and salt stress (64), and by biotic agents
(81, 120).
Other factors involved in protein folding
in the ER are molecular chaperones, which aid
in protein folding but do not guide it. Binding
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protein (BiP) is one of the most abundant chaperones in the ER lumen and is thought to bind
nascent proteins entering the ER, preventing
their aggregation (88). This is a critical function
for chaperones because the ER is a crowded
protein-folding environment, and exposed hydrophobic surfaces on nascent proteins make
them vulnerable to aggregation. BiPs are heat
shock 70 proteins that bind ATP and operate
in conjunction with J-domain-containing proteins ( J proteins) (117). J proteins interact with
BiP to stimulate ATP hydrolysis, promoting
the rapid entrapment of polypeptides by BiP;
these polypeptides are then slowly released
upon nucleotide exchange (80).
Nucleus
Cytosol
Stress-response
gene
bZIP28
bZIP60 gene
bZIP60
S2P
Translation
Golgi bodies
S1P
bZIP60 mRNA
Splicing
IRE1
COPII vesicle
components
bZIP28
MEMBRANE-ASSOCIATED
TRANSCRIPTION FACTORS
ER membrane
The first responders to ER stress are ER stress
sensor/transducers located on the ER membrane. Mammalian cells have three classes of
ER sensor/transducers, each heading up an arm
or branch of the UPR signaling pathway (113).
One arm involves membrane-associated transcription factors that, when activated, are released and then relocate to the nucleus to upregulate UPR genes. Another arm is headed up by
a dual-functioning protein kinase/ribonuclease
called inositol-requiring enzyme 1 (IRE1) (see
IRE1 and the RNA-Splicing Arm, below). The
third arm involves a membrane-associated protein kinase called protein kinase RNA-like
endoplasmic reticulum kinase (PERK), which
phosphorylates and inactivates a translation initiation factor, eIF2a, thereby slowing translation. So far, plants have only been shown to have
the first two arms of the ER stress–response
pathway (Figure 1).
In mammalian cells, one of the best-studied
membrane-associated stress-transducing transcription factors is a basic leucine zipper (bZIP)
factor called activating transcription factor 6
(ATF6). ATF6 is a type II membrane protein with a single-pass transmembrane domain,
a bZIP domain facing the cytosol, and a Cterminal tail with a site 1 protease (S1P) cleavage site facing the ER lumen. Following stress
BiP
ER lumen
Misfolded
protein
Figure 1
The two arms of the ER stress–response signaling pathway in plants. One arm
involves membrane-associated transcription factors such as bZIP28; the other
involves a membrane-associated dual-functioning protein kinase/ribonuclease,
IRE1, that splices the mRNA encoding bZIP60. In response to stress, bZIP28
and IRE1 are activated by the accumulation of misfolded proteins in the ER.
bZIP28 is mobilized from the ER and transported to Golgi bodies, where it is
progressively processed by S1P and S2P. S2P intramembrane cleavage releases
the N-terminal component of bZIP28 into the cytosol, allowing it to relocate
to the nucleus. Once activated, IRE1 splices the bZIP60-encoding mRNA,
creating a frameshift such that the spliced RNA now encodes a transcription
factor with a nuclear targeting signal. bZIP28 and bZIP60 can heterodimerize,
and the two arms of the signaling pathway may converge in the formation of
heterodimers that can upregulate stress-response genes.
treatment, ATF6 is mobilized, exiting the ER
and moving to Golgi bodies, where it is subject to proteolysis by two Golgi-associated proteases: S1P (a soluble lumenal protease) and site
2 protease (S2P, a membrane-associated metalloprotease). S2P cleaves ATF6 in the membrane, releasing the cytosolic-facing component with the bZIP domain, which relocates
into the nucleus to upregulate target genes.
www.annualreviews.org • Endoplasmic Reticulum Stress Responses in Plants
Unfolded protein
response (UPR):
response to ER stress
involving the
upregulation of
stress-response genes
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Stress-response
gene
Nucleus
S2P
S1P
Cytosol
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Golgi bodies
bZIP28
COPII vesicle
components
Sar1
ER membrane
BiP
Misfolded
protein
ER lumen
Figure 2
Mobilization of bZIP28 in response to ER stress. bZIP28 is a type II membrane
protein with a single transmembrane domain, an N-terminal domain that
contains transcription factor elements facing the cytosol, and a C-terminal
domain in the ER lumen. bZIP28 is thought to be retained in the ER by the
association of its C-terminal domain with BiP in the ER lumen. Under stress
conditions, BiP is recruited away by the accumulation of misfolded proteins in
the ER, releasing bZIP28. bZIP28 clusters in the ER membrane, associates
with the Sar1 GTPase and other COPII vesicle elements, and is included as
cargo in the transport of materials from the ER to Golgi bodies. bZIP28 is
processed by Golgi-resident proteases, first by S1P and then by S2P, releasing
the N-terminal domain of bZIP28 for relocation to the nucleus.
Tunicamycin: an
antibiotic that inhibits
N-linked glycosylation
and elicits ER stress
responses and the
UPR
Calnexin: a
membrane-bound
component of the
protein-folding
machinery in the ER
Calreticulin: a
soluble component of
the protein-folding
machinery in the ER
lumen
480
bZIP17 and bZIP28
Homologs of ATF6 were identified in Arabidopsis among the 75 members of the bZIP
transcription factor gene family as factors
predicted to be type II membrane proteins.
There were four in this category, three of
which—AtbZIP17, -28, and -49—were much
like ATF6, having a bZIP domain predicted to
face the cytosol and a C-terminal tail with a
canonical S1P cleavage site.
To determine whether these proteins serve
as ER stress sensor/transducers in Arabidopsis, the proteins were epitope or green fluorescent protein (GFP) tagged at their N termini and introduced into transgenic plants (10,
Howell
66). Transgenic plants were then subjected
to ER stress agents and a variety of environmental stress stimuli. bZIP17 was proteolytically cleaved following exposure of transgenic seedlings to high-salt stress or ER stress
agents. Proteolysis required functional S1P and
S2P, although only the S2P cleavage product
was observed. The explanation given was that
S1P cleavage potentiates S2P proteolysis, and
once S1P cleavage occurs, it is followed very
rapidly by an S2P cut, and very little of the intermediate accumulates. Following ER stress
treatment, GFP-tagged versions of bZIP17
were observed to move from the ER to the
nucleus.
bZIP28 follows a similar pattern of activation involving movement to Golgi bodies in response to ER stress, proteolysis by S1P and S2P,
release from Golgi membranes, and relocation
to the nucleus (Figure 1) (65). Because these
bZIP factors move from one organelle to another, Srivastava et al. (103) investigated steps
involved in the exit of bZIP28 from the ER
(Figure 2). In animal systems, transfer of cargo
from the ER to Golgi bodies involves COPII
vesicles, but whether this is the case in plants
is still a matter of debate (30). Plants have numerous, mobile Golgi bodies that are thought
to dock at ER exit sites and pick up cargo without the involvement of intermediate vesicles;
nonetheless, ER-to-Golgi-body trafficking in
plants is still thought to involve the COPII machinery, if only to concentrate cargo at prebudding sites in the ER.
A critical piece of the COPII machinery is
the Sar1 GTPase, which initiates the formation
of prebudding sites. Sar1 is thought to interact
with cargo directly or indirectly through its
interaction with Sec23/24, a COPII vesicle
coat element. Srivastava et al. (103) found that
ER stress in Arabidopsis led to an enhanced association between bZIP28 and Sar1b, a product
of one of the more abundantly expressed Sar1encoding genes in Arabidopsis. Sar1 appears to
interact with a lysine-rich region on the cytosolic side of bZIP28, adjacent to the transmembrane domain. Substitution of lysine residues
in this region with alanines interferes with
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Sar1 association and prevents the exit of GFPbZIP28 from the ER to Golgi bodies (103).
What enhances the interaction between
bZIP28 and Sar1 in response to ER stress is
not known. Sar1 and the lysine-rich region of
bZIP28 are on the cytosolic side of the ER
membrane, but ER stress signals derive from
the ER lumen. In animal cells, ATF6 is thought
to be retained in the ER under unstressed conditions by binding to BiP, which is competed
away or actively dissociated from ATF6 when
misfolded proteins accumulate under ER stress
conditions (97, 98). After ATF6 is liberated
from the ER, it is relocated to Golgi bodies—
only to be cleaved by Golgi-resident proteases
and released into the cytoplasm.
Nucleus
CCAAT bZIP
box binding
BIP3 gene
Cytosol
bZIP CCAAT
binding box
bZIP28
NF-YC2 gene
Importin β?
Golgi bodies
NF-YA4
Importin 13?
Upregulation of Stress-Response
Genes
NF-YB3
NF-YC2
More has been learned about the role of bZIP28
in transcription. Some of the genes upregulated by bZIP28 encode components of the
ER protein-folding machinery, including BIP3,
calnexin, calreticulin, and protein disulfide isomerase (PDI). Many genes in this group share
a common element in their promoters, an ER
stress–response element 1 (ERSE1). ERSE1
is composed of two subelements: a CCACG
subelement that binds bZIP dimers and a
CCAAT subelement that binds CCAAT-boxbinding factors (Figure 3) (122). CCAAT-boxbinding factors are general transcription factors
composed of three nuclear factor Y (NF-Y) subunits: NF-YA, NF-YB, and NF-YC. The Arabidopsis genome has 36 NF-Y-subunit-encoding
genes (100), and it was of interest to identify
which subunits are associated with bZIP28 in
regulating genes through ER stress.
Liu & Howell (63) used a three-hybrid system to identify the subunits of the CCAATbox factor(s) that interact with bZIP28. When
expressed together, NF-YB3 and NF-YC2 interacted strongly with bZIP28. A candidate for
the third subunit, NF-YA4, that interacted with
NF-YB3 and NF-YC2 was inferred from the
yeast interactome (24). The NF-YA4, NF-YB3,
and NF-YC2 subunits, together with bZIP28,
Translation
Figure 3
CCAAT-box-binding factors, which are regulated by ER stress. The ERSE1
elements in the promoters of ER stress–response genes (BIP3 and NF-YC2) are
composed of two subelements: a CCACG subelement that binds bZIP dimers
and a CCAAT subelement that binds CCAAT-box-binding factors, which are
heterotrimeric proteins made up of NF-Y subunits. bZIP28 interacts with a
CCAAT-box factor composed of NF-YA4, NF-YB3, and NF-YC2 subunits.
The genes encoding NF-YA4 and NF-YB3 are constitutively expressed in
Arabidopsis seedlings, but the gene encoding NF-YC2 is not. That gene is
upregulated by ER stress in a manner that is partially dependent on bZIP28.
Although the gene encoding NF-YB3 is constitutively expressed, the protein is
located outside the nucleus under unstressed conditions. NF-YB3 is thought to
be imported into the nucleus as a dimer following its heterodimerization with
NF-YC2.
all synthesized in Escherichia coli, successfully assembled into a complex in vitro in the presence of a double-stranded oligonucleotide representing an ERSE1 protein (63).
Siefers et al. (100) had earlier used promoter:reporter constructs to show that
NF-YA4 and NF-YB3, but not NF-YC2,
were constitutively expressed in Arabidopsis
seedlings. However, Liu & Howell (63) found
that NF-YC2 expression was upregulated by
ER stress agents and that the upregulation was
dependent in part on bZIP28. Although NFYB3 expression was constitutive, GFP-tagged
www.annualreviews.org • Endoplasmic Reticulum Stress Responses in Plants
Binding protein
(BiP): molecular
chaperone protein that
binds to misfolded
proteins to prevent
their aggregation
Inositol-requiring
enzyme 1 (IRE1): ER
membrane–localized
RNA-splicing factor
activated by ER stress
(the name has little to
do with its function in
plants)
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Basic leucine zipper
(bZIP): transcription
factor that bears a
leucine repeat zipper
involved in protein
dimerization and
DNA binding
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Transmembrane
domain: α-helical
region of a protein
that passes through a
membrane
Site 1 and site 2
proteases (S1P and
S2P): resident
proteases in Golgi
bodies that process
bZIP17 and bZIP28
Nuclear factor Y
(NF-Y): a trimeric
general transcription
factor that functions as
a CCAAT-boxbinding protein
12:55
NF-YB3 was located largely in the cytoplasm
of unstressed seedlings. Following stress
treatment, NF-YB3 relocated to the nucleus.
Hence, Liu & Howell (63) proposed that
following stress treatment, bZIP28 is activated
and upregulates genes such as BIP3 and
NF-YC2 (Figure 3). NF-YB and NF-YC
are histone-fold-containing proteins that heterodimerize, and in mammalian cells they enter
the nucleus as heterodimers through the importin 13 nuclear import system. It is therefore
thought that in Arabidopsis, the upregulation of
NF-YC2 expression promotes NF-YB3 entry
into the nucleus. In mammalian cells, NF-YA is
imported on its own by a different mechanism—
the importin β system—and is then recruited
to form a heterotrimeric CCAAT-box-binding
factor (21, 48). In the nucleus and through its
interaction with bZIP28, the CCAAT-boxbinding factor is likely to reinforce or sustain
the activity of bZIP28. Thus, ER stress activates
both the specific bZIP28 transcription factor
and the general CCAAT-box-binding factor.
IRE1 AND THE RNA-SPLICING
ARM
The second arm of the ER stress–response
pathway in plants involves the RNA-splicing
factor IRE1, a dual-functioning protein kinase/ribonuclease (Figure 1). This arm of the
pathway is thought to be the most ancient arm,
because it is found in yeast, nematodes, fruit
flies, and mammals. Until recently, the arm
had not been described in plants, although two
genes encoding IRE1 had been identified in
Arabidopsis (56).
The RNA-splicing arm was discovered
through efforts to understand the activation
of another ER stress–induced, membraneassociated bZIP transcription factor, bZIP60
(43). bZIP60 had been implicated in ER stress
responses through earlier work by Iwata &
Koizumi (42), who found that the transgenic
expression of an activated form of bZIP60 upregulates the expression of UPR genes. The activated form in their constructs was a truncated
version of the protein that lacked a transmem482
Howell
brane domain and C terminus. From this, they
speculated that the normal endogenous bZIP60
is likely activated by proteolysis.
Proteolytic activation of bZIP60 was also
supported by the observation of a shorter form
of bZIP60 following treatment by ER stress
agents (41). The full-length form was associated with microsomal membranes, whereas the
shorter form was located in nuclei. The only
bZIP60 features that seemed inconsistent with
proteolytic activation were that the full-length
form lacks a canonical S1P site and that the appearance of the shorter form was not dependent
on S1P or S2P. Because of this, it was argued
that the processing of bZIP60 is unique, involving an undescribed proteolytic processing pathway (41, 42).
bZIP60 mRNA Splicing
Subsequently, however, it was shown that transcriptionally active forms of bZIP60 are produced by IRE1-mediated splicing of bZIP60
mRNA, not by proteolysis (16, 82). bZIP60
mRNA was considered to be the RNA-splicing
target for IRE1 because, based on the structure
of the sites in HAC1 mRNA in yeast and XBP1
mRNA in mammalian cells, RNA-folding programs predicted that bZIP60 mRNA can fold
into a consensus IRE1 recognition site (87,
121). The recognition site is composed of a pair
of stem loops with conserved bases at three positions in each loop (Figure 4a). Another feature of these structures is that they are “kissing”
stem loops in which the two stems are capable
of base pairing with each other.
Deng et al. (16) found that bZIP60 mRNA
is spliced in Arabidopsis seedlings in response
to ER stress agents, such as tunicamycin and
dithiothreitol. Splicing excised a 23b segment
of mRNA, causing a frameshift beyond the
splice site (Figure 4a). The splice site was just
upstream of the single transmembrane domain
in bZIP60, and the frameshift eliminated this
domain (Figure 4b). In the new sequence
downstream from the splice site were two
putative nuclear localization signals, and the
authors demonstrated that the GFP-tagged
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form of unspliced bZIP60 mRNA was located
primarily in the cytoplasm, coincident with
ER markers, and the spliced form was located
exclusively in the nucleus.
Deng et al. (16) also conducted experiments
to determine whether RNA splicing is, in fact,
required to activate bZIP60 transcription. They
did so by substituting a conserved base in one of
the twin loops of the IRE1 recognition site. The
substitution blocked bZIP60 mRNA splicing
and inhibited the stress-induced upregulation
of a bZIP60 target gene, BIP3. This demonstrated that RNA splicing, and not proteolysis,
was responsible for bZIP60 activation.
The Arabidopsis genome has three genes
encoding IRE1-like proteins, but only two,
IRE1a and IRE1b, encode full-length proteins.
In two studies, transfer DNA (T-DNA) insertion mutations in IRE1a had little effect on ER
stress–induced splicing of bZIP60 mRNA in
Arabidopsis seedlings in response to ER stress
agents; however, knockout mutations in IRE1b
eliminated most splicing (16, 81). In studies by
Nagashima et al. (82) using seedlings with a different ire1b allele, the single ire1b mutation had
less of an effect on bZIP60 splicing, but double
ire1a ire1b mutants eliminated all detectable
stress-induced splicing. Thus, IRE1a and
IRE1b seem to function somewhat redundantly
in the splicing of bZIP60 in seedlings, although
there may be differences in the assays used to
determine the extent to which they do so.
Converging Pathways
Although bZIP60 and bZIP17/bZIP28 head
up the separate arms of the ER stress pathway,
two observations suggest that the pathways
converge in the regulation of target genes
(Figure 1). First, Liu & Howell (63) showed
that in a yeast two-hybrid system, bZIP60
tends to heterodimerize with bZIP28 and
bZIP17. Second, some genes, such as BIP3,
are partially dependent on both bZIP28 and
bZIP60 for upregulation in response to ER
stress in Arabidopsis (41, 63). From this, it
appears that the pathways for the two arms
a
640
C
A A G C A G
G A G U
U U CG U C
C U C G
U U
U U
U
G
Loop 1 C
U G U
G
C
G G A A U C C
C C U UG G G
Loop 2
U
680
U G
C
U
U G
b
bZIP60
unspliced
140
1
197
295
bZIP
Transmembrane
domain
Cytosol
bZIP60
spliced
ER
membrane
140
1
197
bZIP
258
Figure 4
Splicing of bZIP60 mRNA by IRE1. (a) Double hairpin loop structure in
bZIP60 mRNA recognized by IRE1. The structure has three conserved bases
(shown in blue) in the hairpin loops, and the mRNA is cut in both loops at sites
indicated by arrows. (b) Proteins encoded by the unspliced and spliced forms of
bZIP60 mRNA. The protein encoded by the unspliced form has a single
transmembrane domain and is predicted to be a type II membrane protein in
the ER. The protein encoded by the spliced form has lost its transmembrane
domain, and the new sequence (shown in red ) downstream from the splice site
contains a nuclear location signal.
of the ER stress response in plants might
converge to upregulate target genes.
Moreno et al. (81) recently found that
IRE1a plays a role in establishing the systemic acquired resistance response elicited
by bacterial pathogen infection in Arabidopsis.
They reported that IRE1a is required to
support the secretion of pathogenesis-related
proteins following treatment of plants with
salicylic acid. As a result, ire1a mutants show
enhanced susceptibility to a bacterial pathogen,
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Oligosaccharide
transferase (OST):
enzyme in the ER that
catalyzes the transfer
of lipid-linked
oligosaccharides onto
nascent glycoproteins
UDPglucose:glycoprotein
glucosyltransferase
(UGGT): enzyme
involved in
monoglucosylating the
branched
oligosaccharide on
glycoproteins in the
calnexin/calreticulin
protein-folding cycle
12:55
whereas ire1b mutants are unaffected. They
also demonstrated that the immune deficiency
in ire1a is due to a defect in salicylic-acidand
pathogen-triggered,
IRE1-mediated
cytoplasmic splicing of the bZIP60 mRNA.
How IRE1a operates and what effectors act
downstream are not known.
Although the original observations on
IRE1-mediated splicing of bZIP60 mRNA
were made in Arabidopsis, similar observations
have been made in rice for mRNAs encoding
OsbZIP74 and OsbZIP50 (homologs of AtbZIP60) (31, 72) and in maize for mRNAs encoding ZmbZIP60 (61).
PROTEIN FOLDING AND
N-LINKED GLYCOSYLATION
Because protein misfolding is a major contributor to ER stress, the operation of the
protein-folding machinery is critical for cell
homeostasis. Nascent polypeptides enter the
ER lumen through the Sec61 translocon
complex and enter one of two protein-folding
pathways (Figure 5) (2). One pathway primarily involves the lumenal binding protein BiP. In
this pathway, there are observations to suggest
that an ER-localized heat shock 40 protein,
ERdj3, binds directly to the nascent protein and
recruits BiP (47). In mammalian cells, BiP associates with other ER proteins, including stromal
cell-derived factor 2 (SDF2)–like 1 (SDF2-L1),
to form a large multiprotein complex (78).
The other folding pathway is N-glycan dependent and involves the calnexin/calreticulin
protein-folding cycle. Nascent polypeptides
bearing glycosylation sites are glycosylated
upon entry by a multisubunit oligosaccharide
transferase (OST), which transfers a preassembled lipid (dolichol)–linked oligosaccharide
onto context-dependent asparagine residues in
glycoproteins (90). ER stress can be induced by
blocking N-linked glycosylation with ER stress
agents such as tunicamycin, an inhibitor of a
key step in the formation of the lipid-linked
oligosaccharide, catalyzed by OST. Koizumi
et al. (57) demonstrated that, in fact, tunicamycin generates ER stress by blocking the
484
Howell
action of OST, because overexpression of OST
confers higher levels of tunicamycin resistance
in Arabidopsis. Inhibition of N-linked glycosylation is probably not physiologically relevant,
although a mutation in one of the subunits of
OST (STT3) in Arabidopsis results in greater
sensitivity to high salt, a condition that also generates ER stress (55). Nonetheless, the effects of
tunicamycin demonstrate that N-linked glycosylation is very important in the protein-folding
process and the elicitation of ER stress.
The lipid (dolichol)–linked oligosaccharides transferred to glycoproteins in plants are
branched structures made up of three glucoses,
nine mannoses, and two N-acetylglucosamines
(Glc3 Man9 GlcNAc2 ) (Figure 6) (33). The
transferred oligosaccharide, which is composed
of three chains (A, B, and C), is modified at
various steps in protein folding (Figure 5).
The modifications on the A chain are signals
interpreted by the protein-folding machinery,
whereas those on the B and C chains provide indicators for ERAD or export (94). The first step
in the modification of the transferred oligosaccharide involves the rapid removal by glucosidase I of the outermost glucose residue on the A
chain, the α-1,2-linked glucose 14. That is followed by the removal of the α-1,3-linked glucose 13 by glucosidase II (19), resulting in a
monoglucosylated oligosaccharide (Figure 6).
These steps are cotranslational, occurring in a
protected environment created by the close association of the Sec61 translocon, OST, glucosidase I and II, and other lumenal factors to
prevent the aggregation of nascent polypeptide
chains (94).
The monoglucosylated oligosaccharide is
recognized by the lectin chaperones calnexin
and calreticulin, which are the principal components of the ER protein-folding apparatus
(Figure 5). Calnexin, a membrane-anchored
protein, and calreticulin, a lumenal protein,
create a folding cage to maintain client proteins
in a folding-competent state. Client proteins
are released by further action of glucosidase
II, which cleaves off glucose 12 by its α-1,3
bond to the A chain. However, proteins
that are not properly folded are sensed by
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Glycosylated
protein
Nonglycosylated
protein
mRNA
Ribosome
Cytosol
Ribosome
Translocon
Translocon
ER lumen
GGG
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OST
ERdj3
Glucosidase I and II
PDI
UGGT
BiP
SDF2
S
PDI
S
Glucosidase II
Calreticulin
S
S
S
Secretion
S
G
Figure 5
Two paths for folding of glycosylated and nonglycosylated soluble proteins in the ER. Protein synthesis
occurs on ER membrane–bound ribosomes, and the growing polypeptide chain is cotranslationally extruded
through the Sec61-like translocon. Glycosylated proteins are glycosylated by the transfer of a lipid-linked
branched oligosaccharide to asparagines at glycosylation sites on the polypeptide by OST. The two terminal
glucosyl residues on the A branch of the oligosaccharide are removed by glucosidase I and II, leaving a
monoglucosylated form of the oligosaccharide side chain that binds to the lectin calreticulin. Calreticulin
and PDI constitute a protein-folding apparatus that subjects nascent proteins to rounds of protein folding.
The terminal glucosyl residue on the A branch of the oligosaccharide is cleaved off by glucosidase II at each
round of the folding cycle, and proteins subjected to additional folding cycles are reglucosylated by UGGT.
On the other path, the DNA J protein ERdj3 binds nascent chains of nonglycosylated proteins as they
emerge in the ER lumen from the translocon. ERdj3 hands off the binding to BiP, which forms a complex
with other factors, including SDF2. PDI also interacts with nonglycosylated proteins in the formation of
disulfide bridges. Successfully folded glycosylated and nonglycosylated proteins are picked up as cargo for
further transport through the secretory pathway.
UDP-glucose:glycoprotein glucosyltransferase
(UGGT) and are reglucosylated to reenter the
calnexin/calreticulin-mediated folding cycle
for additional rounds of folding. UGGT plays
the role of a decision maker in ERQC by recognizing clusters of surface-exposed hydrophobic
residues in molten globule-like conformers in
unfolded protein domains (8, 102, 109).
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14
α-1,2
13
A
α-1,3
B
*
C
12
A
B
C
7
9
11
6
8
10
A
B
C
12
α-1,3
7
α-1,2
9
11
α-1,2
α-1,2
6
α-1,2
10
8
α-1,3
4
10
α-1,6
5
α-1,3 3
*
8
α-1,6
4
5
4
5
3
3
2
2
1
1
1
a
b
c
β-1,4
Glc
2
β-1,4
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Man
GlcNAc
Figure 6
Structure of the branched oligosaccharide chains on glycoproteins. (a) The core oligosaccharide
(Glc3 Man9 GlcNAc2 ) contains three branches (A, B, and C). Residues are numbered by order of addition
during biosynthesis. (b) The monoglucosylated form of the core oligosaccharide (Glc1 Man9 GlcNAc2 ) binds
to calnexin/calreticulin during protein folding. This form is produced by the removal of the terminal
α-1,2-glucose 14 by glucosidase I and the removal of the α-1,3-glucose 13 by glucosidase II. During
protein-folding cycles, the terminal α-1,3-glucose 12 on the monoglucosylated form (indicated with an
asterisk) is progressively removed and readded by glucosidase II and UGGT, respectively. (c) The partially
demannosylated form (Man5 GlcNAc2 ) targets glycosylated proteins to ER-associated degradation (ERAD).
The terminal α-1,6-mannose 10 on the C chain is the signal recognized by the lectin OS9 for targeting to
ERAD.
Associated with calnexin/calreticulin cages
in yeast are PDIs that catalyze the formation of
conformation-stabilizing disulfide bonds (36).
PDIs catalyze not only the formation of disulfide bonds but also the isomerization or reshuffling of nonnative bonds as proteins acquire
their native state. The Arabidopsis genome encodes 12 PDIs, of which 9 have signal peptides
and ER retention signals (71). PDIs require
different redox couples to oxidize cysteines in
the formation of disulfide bonds and to reduce
nonnative bonds during isomerization (4). In
yeast, the principal redox couple that provides
oxidizing equivalents for disulfide bond formation involves ER oxidoreductase 1 (Ero1p), for
which Arabidopsis has two homologs, AERO1
and AERO2.
Glycoproteins are extracted from the folding machinery by the cleavage of α-1,2mannosyl residues by α-mannosidases (class 47
glycosyl hydrolases) (Figure 7) (1). Ubiquitin486
Howell
protein ligases of the ERAD system recognize
misfolded glycoproteins through a bipartite
signal—exposed hydrophobic protein patches
and an exposed α-1,6-linked mannose on the
oligosaccharide C chain—and direct them to
disposal in the cytosol (34).
ER-ASSOCIATED DEGRADATION
The degradation of misfolded proteins by the
ERAD system is key in reestablishing homeostatic equilibrium in response to ER stress (32).
All eukaryotic cells possess an ERQC system to
identify and dispose of unfolded or misfolded
proteins in the secretory pathway. In humans, a
growing number of diseases, such as Huntington’s and Parkinson’s diseases, are attributed
to defects in secretory protein folding and in
the elimination of misfolded proteins (25).
ERAD involves four fundamental steps:
recognition, ubiquitination, retrotranslocation,
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and degradation of proteins to be eliminated.
Recognition of misfolded proteins for degradation by the ERAD system is a challenge considering the different protein substrates with
which the ERQC system must contend. The
recognition system involves E3 ubiquitin ligases equipped with adapters that endow the
ligases with remarkable recognition capacities
(101). In yeast, the ERQC surveillance system examines three categories of substrates (6):
ERAD-L monitors soluble lumenal proteins or
membrane proteins with regions that extend
into the ER lumen (as in Figure 7), ERAD-M
deals with membrane proteins with misfolded
domains within the membrane, and ERAD-C
inspects membrane proteins with regions that
extend into the cytosol.
How are nascent glycoproteins in the
process of being folded distinguished from
terminally misfolded proteins? In yeast, most
ERAD-L substrates are handled by the Hrd1
complex; this complex is made up of Hrd3 E3
ubiquitin ligase and Yos9 lectin, which together
interrogate both the sugar and folding status
of glycoproteins. Yos9 recognizes the terminal
α-1,6-mannose linkage on the C chain of the
N-glycan of a glycoprotein (Figure 6c), which
has been exposed during folding by the action
of homologous to mannosidase 1 (Htm1), a
class 47 glycosyl hydrolase, in combination
with PDI (23). This step involves the bipartite
recognition of the terminal α-1,6-linked
mannose on the C chain and the misfolded
protein moiety (17). Therefore, the Hrd1 complex spares nascent glycoproteins from early
degradation, and misfolded proteins bearing
modified glycans are consigned to ERAD
(23).
Proteins that report on the function of the
ERAD system and/or chronically misfolded
proteins are important tools in the study of the
ERAD and ERQC systems. In animal cells,
chronically misfolded proteins that are targeted
for ERAD and that elicit ER stress include
defective forms of the cystic fibrosis transmembrane conductance regulator (CFTRF508,
a chloride channel protein) and defective
forms of soluble lumenal proteins such as
Ribosome
ebs5 HRD3
Translocon
OST
CDC48
Cytosol
Ub
Ub
Ub
ebs6 OS9
GGG
26S
proteasome
HRD1
S
ERAD
PDI
S
ebs1
UGGT
α-Mannosidase
S
Glucosidase II
ebs2
Calreticulin
ER lumen
G
Figure 7
ER-associated degradation (ERAD) mechanism for the degradation of a
hypothetical misfolded, soluble glycoprotein in the ER. As in Figure 5,
glycoproteins are synthesized on membrane-bound ribosomes, threaded
through the Sec61-like translocon, and glycosylated by OST.
Monoglucosylated proteins bind to the lectin calreticulin and are subjected to
rounds of protein folding. If the glycoprotein fails to acquire its native state,
then α-mannosidase purportedly interrupts the futile folding cycles by
removing the terminal α-1,6-linked mannose on the C branch of the core
oligosaccharide. The mannose-trimmed misfolded glycoprotein is recognized
by the lumenal lectin OS9 in collaboration with HRD3, a membrane-spanning
protein, and recruited as a client protein for cytosolic ubiquitination by the E3
ligase HRD1. The misfolded protein is thought to be extracted from the ER
lumen by CDC48 (an AAA-ATPase motor) and then targeted to the 26S
proteasome.
carboxypeptidase yscY (CPY∗ ), mutant α-(1)antitrypsin, and unassembled immunoglobulin
heavy chains. In plants, expression of a
truncated form of the bean storage protein
phaseolin fails to assemble and elicits ER stress,
as indicated by its association with BiP (91)
Genetic and biochemical analyses of the determinants that aid in the folding or elimination
of these reporters have revealed components
of the protein-folding and ERAD machinery.
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Brassinosteroid
insensitive 1 (BRI1):
the brassinosteroid
receptor that signals
plant growth in
response to the steroid
hormone
Asparagine-linked
glycosylation (ALG):
group of factors
involved in the
synthesis of
lipid-linked
oligosaccharides
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12:55
In plants, altered hormone or pathogen receptors that are detained by the ERQC system
have provided convenient readouts for the function of the ERAD and ERQC systems. Li and
coworkers (38) utilized mutant brassinosteroid
receptors, such as brassinosteroid insensitive 19 (bri1-9) (S662F) and bri1-5 (C69Y), which
are functionally competent as hormone receptors but are interpreted by the ERQC system as
ERAD substrates. These receptor mutants are
dwarfs, because the brassinosteroid receptors
are degraded by ERAD. The investigators then
used these mutants to identify nondwarf plant
suppressors that allow the receptors to leak
through the ERQC system and emerge where
they function in brassinosteroid perception.
One of the first suppressors identified, ebs11, had a defect in UGGT, the activity that
reglucosylates the core oligosaccharides on glycoproteins in the calnexin/calreticulin proteinfolding cycle (Figure 7) (46). UGGT plays an
important role in ERQC because reglucosylation sends partially unfolded proteins back for
additional rounds of protein folding. The defective UGGT apparently fails to detain BRI19 in futile rounds of protein folding and allows
it to leak through.
Another suppressor (ebs2) derived from this
selection scheme was a calreticulin, specifically
calreticulin 3 (CRT3) (Figure 7) (45). Again,
ebs2 is thought to act as a suppressor in that
without CRT3 function, BRI1-9 is thought to
escape from futile protein-folding cycles and
emerge on the cell surface as a functional brassinosteroid receptor. It is interesting that the
lumenal protein CRT3, and not the membraneassociated calnexin, is involved in the ER retention of BRI1-9, which is a membrane protein,
albeit one with a large lumen-facing domain.
Both calnexin and CRT3 have been shown to
interact with BRI1-9 (45, 46). It is also of interest that BRI1-9 is a client for CRT3 and not
CRT1 or -2, two other calreticulin isoforms
in Arabidopsis. However, CRT3 is phylogenetically distinct from CRT1 and -2 (44).
Another suppressor (ebs5) encodes a homolog of yeast Hrd3 (or, as it is called in
mammalian cells, Sel1L) (Figure 7) (104). As
Howell
described above, Hrd3 is an adapter in the Hrd1
complex that ubiquitinates misfolded proteins
(58), thereby identifying them for ERAD disposal. Hrd3 is an integral membrane protein
with a large lumen-facing domain that senses
exposed hydrophobic surfaces on misfolded
proteins (18). Su et al. (104) found that EBS5
in plants binds (coimmunoprecipitates with) the
misfolded BRI1 receptors (BRI1-9 and BRI1-5)
but not the wild-type BRI1 receptor, demonstrating that EBS5 is capable of recognizing
misfolded proteins. In the same study, the authors also identified two Arabidopsis genes that
are homologs of yeast Hrd1. They found that
the two have overlapping function and that a
knockout of both genes suppresses the bri1-9
phenotype.
Yet another suppressor (ebs4) encodes
a mannosyltransferase, a putative ortholog
of yeast asparagine-linked glycosylation 12
(ALG12), which is involved in the assembly of
lipid-linked oligosaccharides (37). This mutant
fails to add α-1,6-linked mannose to the C
chain of the oligosaccharide and transfers
incompletely assembled oligosaccharides to
glycoproteins. When exposed, this α-1,6linked mannose is the critical glycan mark
for an ERAD client recognized by the lectin
OS9 (Figure 6c) (12, 93). Recently, the OS9
homolog in Arabidopsis (AtOS9) was identified
through a T-DNA insertion mutation and the
suppressor ebs6-1 (Figure 7) (39, 105). AtOS9
was found to interact biochemically and genetically with EBS5 or HRD1. Without the exposed α-1,6-linked mannose or with a defect in
AtOS9, the BRI1 receptors in bri1-9 and bri1-5
escape ERAD to become functional receptors.
These two suppressors emphasize the importance of the oligosaccharides on glycoproteins
in the functioning of the ERAD system.
Another system that has served to report
on the function of the protein-folding and
ERQC systems involves the maturation of
an Arabidopsis leucine-rich-repeat receptor
kinase (LRR-RK), which plays a role in plant
innate immunity (60). The maturation of
the pathogen receptor LRR-RK elongation
factor Tu receptor (EFR) that recognizes the
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bacterial EFR has been shown to be dependent
on the ERQC. Nekrasov et al. (84) identified
Arabidopsis elfin mutants defective in their
response to the EF-Tu surrogate peptide elf18.
Several studies of the elfin mutants revealed
mutations in the protein-folding machinery
and in the ERQC system, including mutations
in CRT3, UGGT, glucosidase IIα and IIβ,
STT3A (a component of OST), SDF2, and
the HDEL retention factor ERD2b (60, 73,
84, 95). The maturation of another receptor,
LRR-RK FLS2, was not affected by most of the
mutations affecting LRR-RK ELF2, indicating
that the two receptors are subject to different
protein-folding and ERQC systems. It was
curious that mutations in the HDEL receptor
family member (ERD2b) also resulted in an elfin
phenotype; however, it was shown the ERD2b
was required to retain CRT3 in the ER (60).
ER STRESS AND AUTOPHAGY
Some of the first responses to ER stress are cellsparing actions. The UPR serves to mitigate ER
stress damage by upregulating the expression
of genes encoding protein-folding and ERAD
components. Autophagy (macroautophagy) is
also a cell-sparing process, one that clears out
whole organelles or pieces thereof and conveys
them to the lysosome compartment for degradation. The process involves sequestration of
cytoplasmic components through the formation of a double-membrane structure called the
phagophore that expands and closes on itself
to form an autophagosome. Autophagosomes
then fuse with lysosomes to form autolysosomes
whose inner membrane and content are degraded (118, 119). A recent review (67) has further described autophagy in plants.
ER stress induces autophagy in mammalian
cells, and the two processes are thought to be
linked by signals from IRE1. Ogata et al. (86)
examined mouse embryonic fibroblast cells deficient in IREα, IRE1αβ, or PERK as well
as ATF6αβ knockdown cells and found that
both IRE1α- and IRE1αβ-deficient cells failed
to induce autophagy in response to ER stress
treatment. The ribonuclease activity of IRE1
was not required for ER stress induction of autophagy, because IRE1 constructs lacking the
ribonuclease domain supported the response.
However, a functional kinase domain was required for ER stress induction of autophagy.
In response to ER stress in mammalian cells,
IRE1 is thought to set off a phosphorylation
cascade that activates the c-Jun N-terminal
kinase ( JNK) pathway. Urano et al. (110)
observed that JNK activity increased when rat
pancreatic acinar cells were treated with ER
stress agents but not when fibroblast cell lines
from an IRE1α knockout mouse were similarly
treated. They attempted to determine which
factors mediate the JNK response, and used
a yeast two-hybrid system to show that tumor
necrosis factor (TNF) receptor–associated
factor 2 (TRAF2) interacted with IRE1α
(110). They further observed that in mammalian cells, TRAF2 interacted with IRE1α
only when the cells were treated with stress
agents. Nishitoh et al. (85) found that the
mitogen-activated protein kinase kinase kinase
(MAPKKK) apoptosis signaling-regulating
kinase (ASK1) is a mediator of TRAF2-induced
JNK activation in the TNF signaling pathway,
and it is assumed that this interaction supports
signaling between IRE1 and JNK in ER stress
responses. Furthermore, Ogata et al. (86)
showed that JNK activation is indeed required
for ER stress–induced autophagy, because the
JNK inhibitor SP600125 blocked autophagy in
mouse embryo fibroblast cells subjected to ER
stress treatment but not in cells subjected to
other treatments that induce autophagy, such
as nutrient deprivation. What is JNK doing
in animal cells to elicit autophagy? The IRE1
arm of ER stress leads to JNK activation and
increases phosphorylation of Bcl-2, promoting
its dissociation from beclin 1, which acts as an
essential activator of the autophagy-inducing
lipid kinase Vps34 (59).
In yeast, 30 genes encoding autophagyrelated (Atg) proteins involved in the formation
of the autophagosome have been identified.
Two of these are ubiquitin-like proteins; one,
Atg12, is conjugated first to Atg7 (an E1-like
protein), then to Atg10 (an E2-like protein),
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Autophagy-related
(Atg) proteins:
proteins involved in
the various steps of
autophagy
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ER stress
IRE1
?
bZIP28
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BI-1
bZIP60
Autophagy
RIDD?
Chaperones
ERAD components
Cell survival
Cell death
Figure 8
Possible pathways leading from ER stress to cell
survival or cell death. ER stress activates IRE1 and
bZIP28. IRE1 splices the mRNA encoding bZIP60,
which is then synthesized as an active transcription
factor. IRE1 also signals the activation of autophagy.
bZIP28 and bZIP60 upregulate ER stress–response
genes that encode chaperones, ER-associated
degradation (ERAD) components, and other
protein-folding factors. These factors and
autophagy reestablish homeostasis and contribute to
cell survival. bZIP28 and bZIP60 also upregulate
BI-1, which has been reported to downregulate
IRE1 in animal systems. Severe ER stress conditions
lead to cell death by less defined pathways, such as
unrestrained autophagy, which results in the
vacuolization of most cellular components and cell
death. In animal systems, severe ER stress is also
thought to evoke more promiscuous activity by
IRE1, which degrades mRNAs on membrane-bound
ribosomes involved in the synthesis of a variety of
secreted proteins. This process is called regulated
IRE1-dependent decay (RIDD). The more
speculative steps in these pathways are indicated by
dashed lines; the activities presumed to occur under
severe ER stress are indicated by red dashed lines.
Programmed cell
death (PCD): a
regulated process by
which cells die
490
and finally to Atg5. The Atg12-Atg5 conjugate
further interacts with a coiled-coil protein,
Atg16, to form a tetrameric Atg12-Atg5·Atg16
complex. Similarly, Atg8 undergoes a series
of ubiquitin ligase-like conjugations until the
Atg12-Atg5 conjugate facilitates the lipidation
of Atg8 and directs it to the developing
autophagosome. The lipidated form of Atg8 is
probably a scaffold protein that enables membrane expansion. The core set of ATG genes
Howell
is found in plants, where there may be several
isoforms for some of the genes. For example,
Arabidopsis contains a family of nine ATG8
genes. ATG8 is present in autophagosomes that
are transported to the vacuole, and the recruitment of ATG8s to autophagosomes has been
used as a marker for autophagy in plants (77).
In plants, autophagy is involved in responses
to nutrient-deprivation conditions, oxidative
stress, salt and drought stresses, pathogen infection, and senescence (26, 69, 70, 115, 116).
Liu et al. (68) recently reported that ER stress
also induces the formation of autophagosomes
in Arabidopsis seedlings. Autophagy induced
by ER stress agents such as tunicamycin and
dithiothreitol led to the engulfment of ER
membranes, as demonstrated by the observation that some autophagosomes contain ER
membranes decorated with ribosomes.
Liu et al. (68) found that ER stress did not
induce autophagosome formation in RNA interference (RNAi)–ATG18a seedlings, blocked
in a step normally required for autophagosome formation under nutrient-deprivation
conditions. They also found that knockout
mutations in IRE1b failed to form autophagosomes in response to ER stress, indicating that
IRE1b is a key step in the signaling pathway
connecting ER stress to autophagy (Figure 8)
(68). Interestingly, autophagosome formation
was not blocked by knockouts in bZIP60,
which encodes the mRNA spliced by IRE1,
suggesting that a function of IRE1b other
than its RNA-splicing capacity connects ER
stress to autophagy. Further work is needed to
identify steps downstream of IRE1b that make
this signaling connection.
ER STRESS AND CELL DEATH
In plants, ER stress has been linked not only to
autophagy but also to cell death (40). A common
form of cell death in animal cells is apoptosis,
which involves blebbing of the plasma membrane and engulfment of the blebs by phagocytes. Plant cells do not have a morphological
equivalent of apoptosis; instead, a form of programmed cell death (PCD) called vacuolar cell
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death occurs in which the internal contents of
the cell are engulfed in the vacuole, ultimately
leading to a rupture of the tonoplast and the
release of vacuolar hydrolytic enzymes (111).
Links between ER stress and cell death have
been established by the demonstration that
ER stress agents produce symptoms of PCD
in a variety of plant cells (13, 123). Following tunicamycin treatment, chromatin was observed to condense and fluoresce in terminal
deoxynucleotidyl transferase dUTP nick end
labeling (TUNEL) staining assays used to detect fragmentation of DNA. In addition, genomic DNA showed DNA laddering brought
about by cleavage at internucleosomal sites, a
hallmark of PCD. To further demonstrate that
PCD results from ER stress, Watanabe & Lam
(114) showed that chemical chaperones such as
4-phenylbutyric acid and tauroursodeoxycholic
acid, which reduce the load of misfolded proteins, attenuate PCD symptoms in Arabidopsis.
Connections between ER stress and cell
death were also made through the finding that
a mammalian cell death suppressor called defender against apoptotic cell death 1 (DAD1)
(83) encodes a subunit of oligosaccharide transfer protein (53). Loss of DAD1 function interferes with N-linked glycosylation and leads to
apoptotic cell death in mammalian cells. Homologs of DAD1, which suppress apoptotic cell
death in mammalian cells, have been identified
in rice and Arabidopsis (22, 107). Indeed, dad1
loss-of-function mutations in Arabidopsis result
in accelerated cell death in response to ER stress
elicited by tunicamycin (92).
As described above (see ER Stress and Autophagy), autophagy is a cell-sparing process—
an attempt to save a cell from cell death. Ogata
et al. (86) showed that the balance between autophagy and cell death was tipped in ER stress–
treated mouse embryonic fibroblasts when
autophagy was blocked by 3-methyladenine.
These cells underwent dramatic cell death.
Furthermore, the fibroblasts deficient in a
critical autophagy component, ATG5, showed
an increased tendency for cell death. In plants,
it may be that autophagy is not an alternative
to cell death; rather, there may be a continuum
in which autophagy is cell sparing under mild
stress conditions but leads to cell death under
acute stress conditions. The critical difference
may depend on whether the tonoplasts in
ER-stressed cells remain intact or rupture (27).
The rupture of tonoplasts in plant cells is
dependent on the action of vacuolar processing enzymes (VPEs), which have caspase-like
activity. Caspases are cysteine proteases, which
orchestrate the demolition phase of apoptosis
in mammalian cells (108). Hatsugai et al. (29)
showed in a different cell death context that the
disintegration of tonoplasts in response to tobacco mosaic virus infection occurs in Nicotiana
benthamiana leaves. However, it does not occur
in leaves in which VPEs have been silenced.
Thus, the tonoplast rupture depends on VPEs,
and it may be the activation of VPEs that tips
the balance in plant cells. In an interesting recent study, Qiang et al. (92) examined the role
of ER stress and cell death in the colonization
of Arabidopsis roots by the mutualistic fungus
Piriformospora indica. They reported that fungal
infection induced ER stress, as indicated by the
expansion of the ER, but did not elicit the UPR,
i.e., the upregulation of indicators such as BiP,
bZIP28, and bZIP60. As a result, they observed
cell death beginning approximately three days
after infection. However, cell death was not observed in a quadruple vpe-null mutant—again
indicating an important role for VPEs in cell
death.
Cell Sparing or Cell Death?
What, then, might be the difference in the
signals that switch ER-stressed cells from cell
sparing to cell death? When mammalian cells
are subjected to irremediable ER stress, PERK
signaling induces ATF4 to upregulate the
CHOP transcription factor, which inhibits the
expression of the antiapoptotic BCL-2 gene
and upregulates the expression of ERO1a,
an oxidase that causes further damage to
the ER by oxidation (74). Under sustained
ER stress, mammalian cells also activate the
IRE1-JNK pathway as described above. JNK
phosphorylation is reported to activate
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proapoptotic BIM and inhibit antiapoptotic
BCL-2 (99). Therefore, it may be the combination of the CHOP and IRE1 pathways that
pushes cells over the line into the apoptotic
mode (106).
Difference Between Plants
and Animals
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A vast literature supports the view that in
mammalian cells the intrinsic (mitochondrial)
apoptotic pathway is the major cell death pathway induced by ER stress (99). In these cells, the
BCL-2 family of proteins regulates the intrinsic
apoptotic pathway by controlling the integrity
of the outer mitochondrial membrane (11). In
response to ER stress, one or more BH3-only
proteins (which share homology with other
BCL-2 family members only in their BH3 domains) are transcriptionally and/or posttranslationally activated and restrain the action of mitochondrial protecting proteins (e.g., BCL-2,
BCL-XL, MCL-1). This triggers the proapoptotic BAX and BAK proteins, which permeabilize the outer mitochondrial membrane.
However, none of the BCL-2 family members or components of the PERK-CHOP pathway are found in plants. How, then, does ER
stress activate cell death in plants? In addressing that question, it is important to ask whether
the intrinsic pathway is operative in plant PCD.
The evidence supporting this idea derives from
the transgenic expression of the mammalian
proapoptotic factor BAX1, which promotes cell
death in plants (3), whereas expression of antiapoptotic factors such as inhibitor of apoptosis (IAP) prevents it (20, 54). Thus, plant
systems appear to undergo PCD via the intrinsic apoptotic pathway when supplied with
mammalian proapoptotic factors, and are likewise prevented from doing so by mammalian
antiapoptotic factors (20). However, although
mammalian BAX1 promotes cell death in plants
and antiapoptotic factors prevent BAX-induced
cell death, this does not mean that the rest of the
pathway is there in some yet-to-be-discovered
form. It does mean that the entire pathway supported by BCL-2 family members can be bypassed by directly expressing BAX1 through a
transgene.
Plant cells do not have homologs of any of
the components of the PERK-CHOP signaling pathway, and therefore the pathway is not
thought to operate in plants. What, then, might
drive the plant signaling pathways to cell death
under acute ER stress conditions? As described
above, IRE1 is highly specific for substrates
such as the twin-loop structure in bZIP60. At
high levels of ER stress in animal systems, however, IRE1 loses its specificity and begins to degrade ER membrane–associated mRNAs in a
process called regulated IRE1-dependent decay
(RIDD) (Figure 8) (35). RIDD further intensifies ER stress by knocking out the mRNAs
that the UPR has upregulated. Whether there
is a RIDD response in plants subjected to highlevel stress conditions is not known, but this
matter should be investigated.
That still leaves BAX inhibitor-1 (BI-1).
There does not seem to be an intrinsic apoptotic pathway in plants, but there is extensive evidence that BI-1 suppresses cell death in
plants or that plant BI-1-like genes inhibit cell
death in nonplant systems (9, 40, 50–52, 76, 96,
114). With respect to ER stress and cell death,
Lisbona et al. (62) may have offered some clarity on this issue by demonstrating that BI-1
negatively regulates IRE1α in animal cells
(Figure 8). In fact, BI-1 appears to form a stable
complex with IRE1α, decreasing its ribonuclease activity. If that mechanism is operational in
plants, it might explain how BI-1 inhibits ER
stress–induced cell death in the absence of an
apoptotic cell death pathway in plants.
SUMMARY POINTS
1. ER stress results from the accumulation of misfolded proteins in the ER. ER stress
induces the unfolded protein response (UPR).
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2. ER stress can be induced by agents that interfere with protein folding or by adverse
environmental conditions.
3. Two arms of the UPR signaling pathway have been described in plants—one involving
membrane-associated bZIP transcription factors and another involving the splicing of
an mRNA by IRE1.
4. Both arms of the signaling pathway lead to the upregulation of ER stress–response genes.
5. Protein folding in the ER is monitored by an ER quality control system. Proteins that
fail to fold properly are eliminated by ER-associated degradation (ERAD).
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6. ER stress can induce autophagy, a cell survival response. ER stress is linked to autophagy
through the action of IRE1. Severe or prolonged ER stress can induce cell death.
FUTURE ISSUES
1. How can we measure the load of unfolded proteins in the ER under stress conditions?
2. What activates IRE1 and bZIP28? Does activation involve more than the dissociation of
BiP?
3. What acts downstream of IRE1 in signaling autophagy?
4. What roles, if any, do unspliced bZIP60 and inactivated bZIP17 and bZIP28 play in the
ER membrane?
5. How do the two arms of the UPR interact in response to stress? Does the interaction
manifest itself at the target gene level?
6. Is there a third arm of the UPR pathway in plants? Does translation slow in response to
ER stress? If so, does it involve an undiscovered PERK-like protein?
7. What is the capacity of the ERAD system in plants? What factors determine whether a
protein will be eliminated by the ERAD system?
8. What determines whether the outcome of the UPR is cell survival or cell death?
9. What role do ER stress responses play under unstressed conditions at various stages of
plant development?
10. How can this information be used to equip crop plants with greater tolerance to abiotic
and biotic stresses?
DISCLOSURE STATEMENT
The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
Work on ER stress in the Howell laboratory is supported by the National Science Foundation
(IOS90917) and by the Plant Sciences Institute at Iowa State University. I thank Yan Deng and
Renu Srivastava for their critical reading of the manuscript.
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Contents
Annual Review of
Plant Biology
Volume 64, 2013
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Benefits of an Inclusive US Education System
Elisabeth Gantt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Plants, Diet, and Health
Cathie Martin, Yang Zhang, Chiara Tonelli, and Katia Petroni p p p p p p p p p p p p p p p p p p p p p p p p p19
A Bountiful Harvest: Genomic Insights into Crop Domestication
Phenotypes
Kenneth M. Olsen and Jonathan F. Wendel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p47
Progress Toward Understanding Heterosis in Crop Plants
Patrick S. Schnable and Nathan M. Springer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Tapping the Promise of Genomics in Species with Complex,
Nonmodel Genomes
Candice N. Hirsch and C. Robin Buell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89
Understanding Reproductive Isolation Based on the Rice Model
Yidan Ouyang and Qifa Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 111
Classification and Comparison of Small RNAs from Plants
Michael J. Axtell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 137
Plant Protein Interactomes
Pascal Braun, Sébastien Aubourg, Jelle Van Leene, Geert De Jaeger,
and Claire Lurin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
Seed-Development Programs: A Systems Biology–Based Comparison
Between Dicots and Monocots
Nese Sreenivasulu and Ulrich Wobus p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 189
Fruit Development and Ripening
Graham B. Seymour, Lars Østergaard, Natalie H. Chapman, Sandra Knapp,
and Cathie Martin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 219
Growth Mechanisms in Tip-Growing Plant Cells
Caleb M. Rounds and Magdalena Bezanilla p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 243
Future Scenarios for Plant Phenotyping
Fabio Fiorani and Ulrich Schurr p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 267
v
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Microgenomics: Genome-Scale, Cell-Specific Monitoring of Multiple
Gene Regulation Tiers
J. Bailey-Serres p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Plant Genome Engineering with Sequence-Specific Nucleases
Daniel F. Voytas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 327
Smaller, Faster, Brighter: Advances in Optical Imaging
of Living Plant Cells
Sidney L. Shaw and David W. Ehrhardt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 351
Phytochrome Cytoplasmic Signaling
Jon Hughes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 377
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Photoreceptor Signaling Networks in Plant Responses to Shade
Jorge J. Casal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 403
ROS-Mediated Lipid Peroxidation and RES-Activated Signaling
Edward E. Farmer and Martin J. Mueller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 429
Potassium Transport and Signaling in Higher Plants
Yi Wang and Wei-Hua Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451
Endoplasmic Reticulum Stress Responses in Plants
Stephen H. Howell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 477
Membrane Microdomains, Rafts, and Detergent-Resistant Membranes
in Plants and Fungi
Jan Malinsky, Miroslava Opekarová, Guido Grossmann, and Widmar Tanner p p p p p p p 501
The Endodermis
Niko Geldner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 531
Intracellular Signaling from Plastid to Nucleus
Wei Chi, Xuwu Sun, and Lixin Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 559
The Number, Speed, and Impact of Plastid Endosymbioses in
Eukaryotic Evolution
Patrick J. Keeling p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 583
Photosystem II Assembly: From Cyanobacteria to Plants
Jörg Nickelsen and Birgit Rengstl p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 609
Unraveling the Heater: New Insights into the Structure of the
Alternative Oxidase
Anthony L. Moore, Tomoo Shiba, Luke Young, Shigeharu Harada, Kiyoshi Kita,
and Kikukatsu Ito p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 637
Network Analysis of the MVA and MEP Pathways for Isoprenoid
Synthesis
Eva Vranová, Diana Coman, and Wilhelm Gruissem p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 665
vi
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Toward Cool C4 Crops
Stephen P. Long and Ashley K. Spence p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 701
The Spatial Organization of Metabolism Within the Plant Cell
Lee J. Sweetlove and Alisdair R. Fernie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 723
Evolving Views of Pectin Biosynthesis
Melani A. Atmodjo, Zhangying Hao, and Debra Mohnen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 747
Annu. Rev. Plant Biol. 2013.64:477-499. Downloaded from www.annualreviews.org
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Transport and Metabolism in Legume-Rhizobia Symbioses
Michael Udvardi and Philip S. Poole p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 781
Structure and Functions of the Bacterial Microbiota of Plants
Davide Bulgarelli, Klaus Schlaeppi, Stijn Spaepen, Emiel Ver Loren van Themaat,
and Paul Schulze-Lefert p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 807
Systemic Acquired Resistance: Turning Local Infection
into Global Defense
Zheng Qing Fu and Xinnian Dong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 839
Indexes
Cumulative Index of Contributing Authors, Volumes 55–64 p p p p p p p p p p p p p p p p p p p p p p p p p p p 865
Cumulative Index of Article Titles, Volumes 55–64 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 871
Errata
An online log of corrections to Annual Review of Plant Biology articles may be found at
http://www.annualreviews.org/errata/arplant
Contents
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