The Rockefeller University Press
J. Cell Biol. Vol. 197 No. 7 857–867
Correspondence to Randal J. Kaufman: firstname.lastname@example.org
Abbreviations used in this paper: ATF, activating transcription factor; C/EBP,
CCAAT enhancer-binding protein; CHOP, C/EBP homologous protein; eIF2;
eukaryotic translational initiation factor 2; IRE, inositol-requiring transmem-
brane kinase/endoribonuclease; PERK, protein kinase-like eukaryotic initiation
factor 2 kinase; UPR, unfolded protein response; XBP, X-box binding protein.
The endoplasmic reticulum (ER) and ER
The ER is a vital organelle for production of secretory pro-
teins that are synthesized by ER-bound ribosomes and then
modified and folded by a machinery of foldases and molecu-
lar chaperones in the ER lumen. Correctly folded secretory
proteins exit the ER en route to other intracellular organelles
and the extracellular surface. The rates of protein synthesis,
folding, and trafficking are precisely coordinated by an effi-
cient system termed “quality control” to ensure that only prop-
erly folded proteins exit the ER. Misfolded proteins are
either retained within the ER or subject to degradation by the
proteasome-dependent ER-associated protein degradation
(ERAD) pathway or by autophagy. Many diseases result from
protein misfolding caused by gene mutations that disrupt
The ER is the major site for the synthesis of sterols and
phospholipids that constitute the bulk of the lipid components
of all biological membranes. The ER, therefore, plays an essen-
tial role in controlling the lipid composition in membranes,
which, in turn, determines the biophysical properties and func-
tions of cell membranes (Fagone and Jackowski, 2009). ER
membrane expansion generally reflects the increased secretory
capacity of the cell. Lipid homeostasis in membranes main-
tained by the ER is important for normal functions of secretory
cells (Leonardi et al., 2009).
The ER is also the main site for storage of intracellular Ca2+.
The concentration of Ca2+ in the ER lumen can reach 5 mM
(Stutzmann and Mattson, 2011). The majority of ER-luminal Ca2+
is bound to ER molecular chaperones and is required for their
optimal function. In addition, ER Ca2+ release is sensed by mito-
chondria as either survival or apoptotic signals in the cell. De-
regulation of the ER Ca2+ content is reported in a number of
diseases including Alzheimer’s disease, Huntington’s disease,
and polycystic kidney disease (Sammels et al., 2010).
The ER is a highly dynamic organelle and responds to en-
vironmental stress and developmental cues through a series of
signaling cascades known as the unfolded protein response
(UPR; Schröder and Kaufman, 2005). The primary signal that
activates the UPR is the accumulation of misfolded proteins in
the ER lumen (Dorner et al., 1989). As a consequence, the UPR
regulates the size, the shape (Schuck et al., 2009), and the com-
ponents of the ER to accommodate fluctuating demands on pro-
tein folding, as well as other ER functions in coordination with
different physiological and pathological conditions. Recent
studies on the integration of ER stress signaling pathways with
metabolic stress, oxidative stress, and inflammatory response
signaling pathways highlight new insights into the diverse cel-
lular processes that are regulated by the UPR (Hotamisligil,
2010). The accessibility to genetically engineered model organ-
isms has further advanced our understanding of the physiologi-
cal and pathological impacts of the UPR in human physiology
and disease. Here, we summarize the adaptive and apoptotic
pathways mediated by the UPR and discuss how the UPR re-
sponds in different physiological and pathological states.
The adaptive role of the mammalian UPR
In mammals, three ER membrane-associated proteins act as ER
stress sensors (Fig. 1): (1) the inositol-requiring transmembrane
kinase/endoribonuclease 1 (IRE1); (2) the double-stranded
A central function of the endoplasmic reticulum (ER) is to
coordinate protein biosynthetic and secretory activities in
the cell. Alterations in ER homeostasis cause accumulation
of misfolded/unfolded proteins in the ER. To maintain ER
homeostasis, eukaryotic cells have evolved the unfolded
protein response (UPR), an essential adaptive intracellular
signaling pathway that responds to metabolic, oxidative
stress, and inflammatory response pathways. The UPR has
been implicated in a variety of diseases including meta-
bolic disease, neurodegenerative disease, inflammatory
disease, and cancer. Signaling components of the UPR
are emerging as potential targets for intervention and
treatment of human disease.
The impact of the unfolded protein response
on human disease
Shiyu Wang and Randal J. Kaufman
Degenerative Disease Research Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037
© 2012 Wang and Kaufman This article is distributed under the terms of an Attribution–
Noncommercial–Share Alike–No Mirror Sites license for the first six months after the pub-
lication date (see http://www.rupress.org/terms). After six months it is available under a
Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license,
as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
T H E J O U R N A L O F C E L L B I O L O G Y
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JCB • VOLUME 197 • NUMBER 7 • 2012 858
the IRE1 pathway to placental development has not been ad-
dressed. A recent study identified an inhibitor of IRE1 endori-
bonuclease activity that did not alter the cellular response to ER
stress, but did reduce ER expansion in an exocrine cell model of
differentiation. This result suggests that IRE1 may play a more
significant role in ER expansion associated with differentiation
of secretory cell types than with the adaptation to ER stress
(Kaufman et al., 2002; Cross et al., 2012).
PERK is the second arm of the mammalian UPR and is
structurally related to IRE1, with an ER luminal dimerization
domain and a cytosolic kinase domain. The immediate effect of
PERK activation is the phosphorylation of the subunit of
eukaryotic translational initiation factor 2 (eIF2) at Ser51
that attenuates global protein synthesis to decrease protein in-
flux into the ER lumen (Shi et al., 1998; Harding et al., 2000b;
Scheuner et al., 2001). On the other hand, phosphorylation of
eIF2 can change the efficiency of AUG initiation codon utili-
zation (Kaufman, 2004), leading to, for example, preferential
translation of activating transcription factor-4 (ATF4) protein
over other upstream reading frames in the mRNA (Harding
et al., 2000a). ATF4 is a transcription factor that induces ex-
pression of genes involved in ER function, as well as ER stress–
induced apoptosis, ER stress–mediated production of reactive
oxygen species, and an inhibitory feedback loop through de-
phosphorylation of eIF2 to prevent hyperactivation of the
UPR (Harding et al., 2003). PERK was also reported to phos-
phorylate nuclear erythroid 2 p45-related factor 2 (NRF2) to
induce antioxidant response genes including heme oxygenase 1
and glutathione S-transferase (Cullinan et al., 2003). Therefore,
the PERK–eIF2 arm of the UPR acts to preserve redox bal-
ance during ER stress through activation of ATF4 and NRF2.
ATF6 is the third arm of the mammalian UPR that is
an ER-associated type 2 transmembrane basic leucine zipper
(bZIP) transcription factor. ATF6 is a distant homologue of
ATF6 but both are ubiquitously expressed in all tissues.
Upon release from BiP, ATF6 traffics to the Golgi appara-
tus for cleavage by serine protease site-1 (S1P) and metallo-
protease site-2 (S2P) to release the transcription-activating
form of ATF6, pATF6(N) (Schindler and Schekman, 2009).
The pATF6(N) can act independently or synergistically with
XBP1s for induction of UPR target genes. The role of pATF6(N)
in development is apparently minimal because mice lacking
ATF6 are viable without significant abnormalities, although
ATF6-null mice are exquisitely sensitive to ER stress (Wu
et al., 2007; Yamamoto et al., 2010). Although there has not
been a phenotype associated with ATF6 deletion, mice lacking
both ATF6 and ATF6 are embryonic lethal, suggesting they
display functional redundancy in early development (Yamamoto
et al., 2007). Thus, the common role(s) for ATF6 and ATF6 in
development needs to be clarified.
In addition to the core components of the UPR, mam-
mals have also evolved some tissue-specific UPR sensors,
most of which are transmembrane bZIP transcription factors
that are activated by regulated intramembrane proteolysis in a
similar manner to ATF6. To date, several of these proteins in-
cluding cAMP responsive element-binding protein H (CREBH
or CREB3L3), CREB3 (Luman), CREB3L1 (Oasis), CREB3L2
RNA (PKR)–activated protein kinase-like eukaryotic initiation
factor 2 kinase (PERK); and (3) the activating transcription
factor-6 (ATF6). Each UPR sensor binds to the ER luminal
chaperone BiP. When misfolded proteins accumulate in the
ER, they bind to and sequester BiP, thereby activating the sen-
sors (Bertolotti et al., 2000; Ma et al., 2002; Shen et al., 2002).
However, additional mechanisms that initiate and modulate
the activity of individual UPR branches have been reported, in
particular for IRE1 (Gardner and Walter, 2011; Promlek et al.,
2011), which may explain their diverse responses to different
signals and/or in different cell types.
IRE1 is the most conserved branch of the UPR, present
from yeast to humans. Mammalian IRE1 has two homologues,
IRE1 and IRE1. IRE1 is expressed in all cells and tissues,
whereas IRE1 is specifically expressed in the intestinal epithe-
lium. UPR signaling is mainly mediated through IRE1, and
the function of IRE1 in the UPR is still not clear. Activated
IRE1 cleaves a 26-base fragment from the mRNA encoding
the X-box binding protein-1 (XBP1; Yoshida et al., 2001).
Spliced Xbp1 mRNA is translated into a potent transcription
factor, XBP1s, which targets a wide variety of genes encoding
proteins involved in ER membrane biogenesis, ER protein fold-
ing, ERAD, and protein secretion from the cell (Lee et al., 2003;
Acosta-Alvear et al., 2007). Mouse genetic studies showed that
germline deletion of Xbp1 or Ire1 in mice is embryonic lethal
(Reimold et al., 2000; Zhang et al., 2005). Recently, a role
for IRE1 was suggested in the placenta for oxygen/nut-
rient exchange between the maternal and fetal circulation
(Iwawaki et al., 2009). However, the contribution of XBP1 in
Figure 1. ER stress and the unfolded protein response. A number of con-
ditions such as disturbed lipid homeostasis, disturbed calcium signaling,
oxidative stress, inhibition of glycosylation, increased protein synthesis,
and decreased ER-associated degradation can cause ER stress and acti-
vate the unfolded protein response (UPR). The UPR is mediated by three ER
membrane-associated proteins, PERK, IRE1, and ATF6, to induce trans-
lational and transcriptional changes upon ER stress. PERK phosphorylates
eIF2 to attenuate general protein translation and decrease protein efflux
into the ER. Phosphorylated eIF2 also selectively stimulates ATF4 trans-
lation to induce transcriptional regulation of UPR genes. IRE1 cleaves
XBP1 mRNA to a spliced form of XBP1 that translates XBP1s to up-regulate
UPR genes encoding factors involved in ER protein folding and degrada-
tion. ATF6 traffics to Golgi for cleavage by S1P and S2P to release
pATF6(N) that works synergistically or separately with XBP1s to regulate
UPR gene expression.
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The unfolded protein response in human disease • Wang and Kaufman
proposed that ER stress contributes to the pathology of many
human diseases (Kaufman, 2002). Cell death, a physiological
consequence of chronic ER stress, is a key to the pathogenesis
of many diseases including metabolic disease, inflammation,
neurodegenerative disorders, and cancer (Fig. 2). Here, we
describe how the use of animal models has contributed to our
knowledge of how the UPR impacts cellular homeostasis, nor-
mal physiology, and disease pathogenesis.
The UPR in diabetes
Cells that are stimulated to secrete large amounts of protein
over a short period of time are highly dependent on a func-
tional UPR. Upon glucose stimulation, the pancreatic cell
increases proinsulin synthesis up to 10-fold (Itoh et al., 1978).
The PERK–eIF2 arm of the UPR is indispensable for cells
to adapt to large fluctuations in proinsulin synthesis (Harding
et al., 2000b; Scheuner et al., 2001). This is most evident from
characterization of Wolcott-Rallison syndrome in which indi-
viduals require insulin at the age of three years. This autosomal
recessive disease is due to loss-of-function mutations in PERK
that cause cell failure. Similarly, whole body inactivation of
the PERK signaling pathway in mice causes a defect in cell
expansion during neonatal development and hyperglycemia
with reduced serum insulin levels (Harding et al., 2000b;
Scheuner et al., 2001). Conditional deletion of Perk in cells
further supports a homeostatic role for PERK signaling in cell
survival (Cavener et al., 2010). Consistent with these observa-
tions, mice with a Ser51Ala mutation at the PERK phosphory-
lation site in eIF2 in a homozygous state, or in a heterozygous
(BBF2H7), and CREB4 (Tisp40) have been identified in re-
sponse to conventional ER stress inducers (Bailey and O’Hare,
2007). Although the exact mechanisms of their activation are
not fully understood, it appears that they synergize with the
mainstream UPR to expand and/or enhance the diversity of
UPR signaling and fine-tune the ER stress response in a tempo-
ral and/or cell type–specific manner (Zhang et al., 2006).
The apoptotic role of the mammalian UPR
Chronic or severe ER stress activates the UPR leading to apoptotic
death. Most data support the notion that PERK–eIF2–ATF4
signaling is a primary determinant for apoptosis (Rutkowski
et al., 2006). Persistent and/or severe ER stress leads to activa-
tion of the PERK–eIF2–ATF4 pathway and culminates in the
induction of the CCAAT enhancer-binding protein (C/EBP)
homologous protein (CHOP/GADD153), a proapoptotic factor
induced by ER stress (Zinszner et al., 1998). CHOP up-regulates
apoptosis-related genes including DR5 (Yamaguchi and Wang,
2004), Trb3 (Ohoka et al., 2005), BIM (Puthalakath et al.,
2007), and PUMA (Cazanave et al., 2010) to promote cell death
during ER stress. Importantly, CHOP also induces GADD34, a
regulatory subunit of protein phosphatase I to dephosphorylate
eIF2 and reverse attenuation of mRNA translation. The cyto-
toxic effects of CHOP are at least in part through GADD34
because CHOP and GADD34 knockout animals are protected
from ER stress–induced tissue damage (Marciniak et al., 2004;
Malhotra et al., 2008; Song et al., 2008). In addition, selective
inhibitors of eIF2 dephosphorylation that target GADD34 can
rescue cells from protein misfolding stress (Boyce et al., 2005;
Tsaytler et al., 2011). How does translation attenuation divert
cells from a cell death pathway to survival during ER stress?
One hypothesis is that translation attenuation prevents contin-
ued synthesis of unfolded proteins that would exacerbate protein-
misfolding stress in the ER leading to a death response.
Under severe stress, activation of IRE1 was implicated
in cell death mediated by apoptosis signaling kinase 1 (ASK1)
through their interaction with tumor necrosis factor receptor-
associated factor 2 (TRAF2; Nishitoh et al., 2002). It was also
reported that IRE1 indiscriminately degrades ER-localized
mRNAs that can lead to cell death (Hollien et al., 2009; Vecchi
et al., 2009). However, the pro-apoptotic signaling molecule(s)
that targets activation of this indiscriminate RNase activity of
IRE1 has not been identified.
The UPR in health and disease
Many extracellular stimuli and fluctuations in intracellular ho-
meostasis disrupt protein folding in the ER. As a consequence,
the cell uses its ER protein-folding status as an exquisite sensor
to monitor intracellular homeostasis. Pharmacological insults
were initially used to elucidate how cells cope with immediate
and severe challenges to the protein-folding quality control
system. It is now evident that intracellular signaling, such as
insulin anabolic responses, as well as metabolic conditions in-
cluding hyperlipidemia, hyperhomocysteinemia, hyperglycemia,
and inflammatory cytokines all disrupt protein folding in the ER.
As a consequence, UPR activation is observed in many human
diseases and mouse models of human disease. Therefore, it was
Figure 2. UPR signaling in diseases. Pathophysiological conditions such
as hypoxia, elevated levels of fatty acids or cholesterol, oxidative stress,
high or low glucose levels, and inflammatory cytokines induce ER stress and
activate the UPR chronically. UPR signaling is interconnected with oxidative
stress and inflammatory response pathways and involved in a variety of
diseases including metabolic disease, inflammatory disease, and cancer.
The three arms of the UPR, IRE1-XBP1s, PERK-eIF2 phosphorylation-ATF4,
and ATF6 are important for tumor cell survival and growth under hypoxic
conditions. The UPR, IRE1, and PERK can activate c-JUN N-terminal kinase
(JNK) and NFB to promote inflammation and apoptosis that contribute to
inflammation in obesity and pancreatic -cell death in diabetes. In addition,
CHOP production in the PERK pathway exacerbates oxidative stress in
diabetic states and atherosclerosis to aggravate the diseases.
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JCB • VOLUME 197 • NUMBER 7 • 2012 860
The UPR in metabolic syndrome
The identification of genetic and environmental factors involved
in metabolic syndrome have revealed that ER stress can inten-
sify a variety of inflammatory and stress signaling pathways to
aggravate metabolic derangement, leading to obesity, insulin
resistance, fatty liver, and dyslipidemia (Fu et al., 2012). In ad-
dition to cells, hepatocytes and adipocytes also significantly
contribute to glucose and lipid homeostasis in the body.
ER stress is linked with hepatic steatosis, which is due to
either enhanced lipogenesis or decreased hepatic lipoprotein
secretion. Overexpression of the protein chaperone BiP in the
liver, as what may occur upon activation of the UPR, inhibited
activation of the central lipogenic regulator-sterol regulatory
element binding protein (SREBP-1c), alleviated hepatic steato-
sis, and improved glucose homeostatic control in obese mice
(Kammoun et al., 2009). ER stress also inhibits hepatic lipopro-
tein secretion (Ota et al., 2008). Although disruption of any sin-
gle arm of the UPR aggravated steatosis under pharmacologically
induced ER stress, it is not known whether this resulted from
increased hepatic lipogenesis or decreased lipoprotein secre-
tion (Rutkowski et al., 2008; Zhang et al., 2011). XBP1s also
regulates fatty acid synthesis by inducing expression of critical
lipogenic enzymes, including stearoyl-CoA desaturase-1 (Lee
et al., 2008). Interestingly, XBP1s interacts with the Forkhead
box O1 (FoxO1) transcription factor and the regulatory subunits
of PI3K, p85, and p85 to decrease hepatic gluconeogenesis
(Park et al., 2010; Zhou et al., 2011). However, only hypolip-
idemia, but neither hypoglycemia nor hyperglycemia, was ob-
served in Xbp1 liver-deleted mice, suggesting that the regulatory
role of XBP1 in hepatic metabolism is primarily to maintain lipid,
and not glucose, homeostasis.
CREBH, a liver-specific component of the UPR, was
originally identified as a central regulator of the acute phase
response, a finding that first linked ER stress with innate sys-
temic inflammatory responses (Zhang et al., 2006). Although
it was recognized that metabolic control and inflammation were
intimately connected (Reddy and Rao, 2006), a mechanism
was lacking. As part of a transducer of inflammatory responses
in the liver, CREBH was recently demonstrated to also regulate
hepatic lipogenesis, fatty acid oxidation, and lipolysis under
conditions of metabolic stress (Zhang et al., 2012). In addition,
CREBH regulates hepatic VLDL-triglyceride clearance in the
plasma by controlling the activity of lipoprotein lipase (Lpl)
through up-regulating genes encoding Lpl coactivator apolipo-
proteins C2, A4, and A5, respectively, and down-regulating the
Lpl inhibitor Apoc3 (J.H. Lee et al., 2011). The identification of
CREBH as a stress-inducible metabolic regulator is likely sig-
nificant because multiple nonsynonymous mutations in CREBH
produce defective CREBH proteins that were reported in hu-
mans with extreme hypertriglyceridemia (J.H. Lee et al., 2011).
These findings indicate that CREBH is a molecular link between
lipid homeostasis and inflammation. Although CREBH interacts
with ATF6 (Zhang et al., 2006), data indicate that they exert
opposite effects on gluconeogenesis. ATF6 inhibits hepatic
glucose output by competing with CREB for interaction with
CRTC2 (Wang et al., 2009), while CREBH promotes gluconeo-
genic activity in a CRTC2-independent manner via an unknown
state combined with stress of a high fat diet, display cell
loss due to proinsulin misfolding, ER stress, oxidative stress, and
apoptosis (Scheuner et al., 2005). In addition, increased protein
synthesis in cells by removing eIF2 phosphorylation caused
a reduction in insulin production, which was due to ER dysfunc-
tion, oxidative stress, and loss of cells. Strikingly, feeding an
antioxidant diet prevented the cell failure upon increased pro-
insulin synthesis (Back et al., 2009). These findings demonstrate
that translational control of proinsulin through phosphorylation
of eIF2 is required to coordinate proinsulin synthesis with pro-
insulin folding to maintain cell homeostasis. Importantly, an
increase in proinsulin synthesis alone is sufficient to initiate a
series of events including proinsulin misfolding, insulin granule
depletion, loss of glucose-stimulated insulin secretion, and oxi-
dative stress, similar to those observed in type II diabetes
(Huang et al., 2007; Laybutt et al., 2007).
Recent genetic evidence indicates that proapoptotic com-
ponents of the ER stress response exacerbate cell failure in
type II diabetes. Deletion of Chop improved glucose control
and increased cell mass in heterozygous diabetic Akita
mice that express a misfolding-prone Cys96Tyr proinsulin
(Oyadomari et al., 2002). Furthermore, Chop deletion improved
cell function in several mouse models of type II diabetes:
(a) high fat diet-fed heterozygous Ser51Ala eIF2 mice; (b) mice
fed a high fat diet and then given streptozotocin, a compound
that kills cells and induces diabetes; and (c) leptin receptor–
null (db/db) mice. Chop deletion not only protected cells
from apoptosis, but also improved cell function by reducing
oxidative damage and improving protein folding in the ER
(Song et al., 2008).
XBP1 is also required for insulin maturation and secre-
tion. Xbp1 deletion in cells markedly impaired proinsulin
processing and decreased insulin production (A.H. Lee et al.,
2011). Enforced expression of XBP1s, as well as ATF6, in-
hibited insulin expression and ultimately killed cells, indi-
cating the importance of homeostatic control of UPR signaling
in cells (Allagnat et al., 2010). Although a mouse model
with cell deletion in Ire1 has not been reported, it is also
likely required for insulin production, similar to XBP1. How-
ever, it was proposed that activated IRE1 degrades proinsu-
lin mRNA to inhibit insulin production (Lipson et al., 2006;
Han et al., 2009). The significance of this IRE1-mediated
proinsulin mRNA degradation needs to be confirmed in a
Wolfram syndrome, a rare genetic disorder, provides an-
other link between ER stress, cell death, and diabetes. Recent
genome-wide association studies showed that polymorphisms
in WFS1 are associated with impaired cell function and risk
for type II diabetes (Franks et al., 2008). WFS1, a downstream
transcriptional target of XBP1, encodes an ER transmembrane
protein that negatively regulates ATF6 to prevent cell death
as a consequence of prolonged ATF6 activation (Fonseca
et al., 2010). There are reports of ATF6 variants associated
with type II diabetes (Thameem et al., 2006; Chu et al., 2007;
Meex et al., 2007), suggesting ATF6 might also play a role
in cell function, consistent with recent findings that suggest
ATF6 protects cells from ER stress (Usui et al., 2012).
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861The unfolded protein response in human disease • Wang and Kaufman
signals in the intestine (Kaser et al., 2008). In addition, hypo-
morphic variants of XBP1 are associated with ulcerative coli-
tis and Crohn’s disease in humans (Kaser et al., 2008), suggesting
the significance of UPR activation in intestinal epithelial
cells. Presently, this is an intense area of investigation (Kaser
et al., 2011).
The UPR is also involved in innate immune responses. Toll-
like receptor (TLR) 4 and TLR2 specifically trigger phosphoryla-
tion of IRE1 leading to splicing of Xbp1 mRNA (Iwakoshi
et al., 2007). This TLR-dependent Xbp1 mRNA splicing is re-
quired for maximal production of proinflammatory cytokines,
such as interleukin 6 in macrophages (Martinon et al., 2010). In
contrast, TLR signaling inhibits ATF6 and PERK activity as
well as signaling through ATF4 and CHOP in macrophages
(Woo et al., 2009). Another pathogenic effect of chronic ER stress
on activation of inflammatory pathways in macrophages is the
progression of atherosclerosis in the settings of dyslipidemia.
Deletion of Chop lessened advanced lesion macrophage apopto-
sis and plaque necrosis in both the Ldlr/ and ApoE/
models of atherosclerosis (Thorp et al., 2009). However, the
effect of TLR-dependent Xbp1 mRNA splicing on the progression
of atherosclerosis requires further investigation.
The UPR in cancer
The UPR is required for tumor cell growth in a hypoxic envi-
ronment. Inactivation of the PERK pathway by either generat-
ing mutations in the kinase domain of PERK or introducing a
phosphorylation-resistant form of eIF2 impairs cell survival
under extreme hypoxia (Fels and Koumenis, 2006). PERK also
promotes cancer cell proliferation and tumor growth by limiting
oxidative DNA damage through ATF4 (Bobrovnikova-Marjon
et al., 2010). Thus, PERK–phospho-eIF2–ATF4 signaling
is critical for tumor cell proliferation and tumor growth (J. Ye
et al., 2010). Although a fusion protein of CHOP, the down-
stream target of ATF4, with an RNA-binding domain was found
in all cases of an adipose cell–based tumor (myxoid liposar-
coma; Crozat et al., 1993), the function of CHOP in tumorigen-
esis remains unknown.
The IRE1–XBP1 axis of the UPR is also important for
tumor cell survival and growth under hypoxic conditions. In a
mouse glioma model, IRE1 inhibition decreased tumor growth
and reduced angiogenesis and blood perfusion, which corre-
lated with increased overall survival in glioma-implanted re-
cipient mice (Auf et al., 2010). Deletion of Xbp1 increased
sensitivity to hypoxia-induced cell death and reduced tumor
formation (Fujimoto et al., 2007). IRE1–XBP1 transcrip-
tional induction of proangiogenic factors, such as vascular
endothelial growth factor, was suggested to promote tumori-
genesis (Ghosh et al., 2010). Inhibiting the IRE1–XBP1 axis
may be a promising approach for anticancer therapy (Koong
et al., 2006). Treatment with STF-083010, a selective inhibi-
tor of the IRE1 RNase activity, demonstrated significant
antimyeloma activity in human multiple myeloma xenografts
(Papandreou et al., 2011). MKC-3946, another small mole-
cule that inhibits IRE1-mediated XBP1 splicing, was also
reported to strongly suppress multiple myeloma cell growth
in vivo (Mimura et al., 2012). In addition, ATF6 plays a pivotal
mechanism (Lee et al., 2010). In obese (ob/ob, db/db) mice,
elevated gluconeogenesis was at least in part attributed to de-
creased levels of ATF6 resulting from chronic ER stress in
obese livers (Wang et al., 2009).
Adipocyte differentiation is a crucial step in body weight
gain. UPR activation including eIF2 phosphorylation and
splicing of Xbp1 mRNA was detected during adipogenesis. In
addition, attenuation of ER stress by treatment with the chemi-
cal chaperone 4-phenylbutyrate (4-PBA) inhibits adipogenesis
(Basseri et al., 2009). Thus, the ER stress–induced UPR appears
to be a stimulus for adipogenesis that requires the IRE1–XBP1
pathway to enhance the expression of the key adipogenic factor
C/EBP (Sha et al., 2009). On the other hand, CHOP inhibits
adipogenesis by interfering with C/EBP action (Batchvarova
et al., 1995). Therefore, the two arms of the UPR apparently
exert opposite effects on adipogenesis, raising the question as
to how the UPR coordinates adipocyte differentiation in vivo.
Further studies are required to address this issue.
Accumulating evidence indicates that ER stress contributes
to the development of insulin resistance in obesity. Treatment of
obese and diabetic mice with the chemical chaperones PBA or
taurine-conjugated ursodeoxycholic acid (TUDCA) alleviated
ER stress–induced activation of c-JUN N-terminal kinase, cor-
rected hyperglycemia, and improved systemic insulin sensitivity
(Ozcan et al., 2006). PBA treatment also improved glucose toler-
ance in insulin-resistant humans (Xiao et al., 2011) and TUDCA
improved insulin sensitivity in liver and muscle, but not adipose
tissue, in obese men and women (Kars et al., 2010). Heterozy-
gous Xbp1-deleted mice develop advanced diet-induced insulin
resistance due to unresolved ER stress coupled with a compro-
mised UPR (Ozcan et al., 2006). In contrast, BiP heterozygosity
attenuated diet-induced obesity and insulin resistance associated
with an activated UPR (R. Ye et al., 2010). However, deletion of
BiP in the liver is extremely toxic, creating tremendous ER stress
and hyperactivation of the UPR (Ji et al., 2011). Therefore, the
UPR may be a binary switch between beneficial and detrimental
effects to maintain metabolic homeostasis.
The UPR in infectious and inflammatory
The role of the UPR in viral infection was well studied in the
last decade. Viruses that express high levels of glycoproteins
activate IRE1 and PERK. PERK-mediated eIF2 phosphor-
ylation is a frontline defense to viral replication in the host
through repressing viral protein synthesis (Cheng et al., 2005).
The role of XBP1s in the immune response was first recognized
as its description as an essential transcription factor for the
differentiation of mature B cells to plasma cells, where XBP1s
expands the ER to support a large amount of immunoglobulin
synthesis (Reimold et al., 2001). Interestingly, activation of
IRE1 was required not only for B cell differentiation, but also
for B lymphopoiesis in the early stages, suggesting IRE1 serves
additional functions other than splicing XBP1s early in B cell
lymphopoiesis (Zhang et al., 2005). Recently, XBP1 was shown
to play a protective role in inflammatory bowel disease. Deletion
of Xbp1 compromised ER protein folding capacity to impair anti-
microbial peptide production and elevated mucosal inflammatory
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JCB • VOLUME 197 • NUMBER 7 • 2012 862
Most significantly, the success of proteasome inhibition
with bortezomib in multiple myeloma (Dimopoulos et al., 2011)
supports the notion that targeting protein homeostasis may be
therapeutic in a number of cancers that are associated with
excessive expression of secretory proteins, such as epithelial
survival role for dormant tumor cells through activation of
mTOR signaling (Schewe and Aguirre-Ghiso, 2008). Increased
expression of BiP/GRP78, which is primarily regulated by ATF6,
correlates with chemotherapeutic resistance and is observed in
aggressive cancers (Lee, 2007).
Table 1. Physiological functions of UPR components in mouse models and their genetic association with human disease
Gene Factors that
Phenotypes of knockout
Genetic association with
N.A. (1) Embryonic lethality at E12.5
due to liver hypoplasia;
(2) Liver deletion: hypolipidemia
(1) Embryonic lethality at E13.5
due to liver hypoplasia;
(2) Liver deletion: hypolipidemia;
(3) Intestinal epithelial cell deletion:
enteritis; (4) Pancreatic acinar cell
deletion: extensive pancreas regenera-
tion; (5) Pancreatic cell deletion:
hyperglycemia; (6) Neuron deletion:
(1) Susceptible to pharmacologically
induced ER stress
(1) Human somatic cancersZhang et al., 2005,
et al., 2007
Kakiuchi et al., 2003b,
2004; Kaser et al.,
2008; Yilmaz et al.,
XBP1sXBP1s and ATF6
(1) Inflammatory bowel disease;
(2) Schizophrenia in the Japanese
population; (3) Bipolar disorder;
(4) Ischemic stroke
N.A. (1) Type 2 diabetes and pre-diabetic
traits; (2) Increased plasma
(1) Extreme hypertriglyceridemia
Chu et al., 2007;
Wu et al., 2007;
Meex et al., 2009
Zhang et al., 2006;
Vecchi et al., 2009;
J.H. Lee et al., 2011
(1) Hypoferremia and spleen iron
sequestration; (2) Hyperlipidemia;
(3) Liver knockdown: fasting
(1) Neonatal hyperglycemiaPERKN.A. (1) Wolcott-Rallison syndrome;
(2) Supranuclear palsy
Delépine et al., 2000;
Höglinger et al., 2011
Elefteriou et al., 2006;
Costa-Mattioli et al.,
et al., 2008
Oyadomari et al., 2002;
Marciniak et al., 2004;
Silva et al., 2005;
Song et al., 2008
ATF4CHOP(1) Delayed bone formation;
(2) Severe fetal anemia;
(3) Increased insulin sensitivity;
(4) Defects in long-term memory
(1) Protected from pharmacologically
induced ER stress;
(2) Protected from type 2 diabetes;
(3) Protected from atherosclerosis;
(4) Protected from leukodystrophy
(1) Diabetes due to insufficient insulin
secretion; (2) Growth retardation
CHOP ATF4 and ATF6
(1) Early-onset type 2 diabetes
WFS1XBP1s (1) Wolfram syndrome;
(2) Risk of type 2 diabetes in
Japanese and European populations
Karasik et al., 1989;
Inoue et al., 1998;
Ishihara et al., 2004;
Mita et al., 2008
Hjelmqvist et al., 2002;
Breslow et al., 2010;
McGovern et al., 2010
Kakiuchi et al., 2005;
Luo et al., 2006;
R. Ye et al., 2010
ORMDL3N.A. N.A. (1) Ulcerative colitis;
(2) Risk of childhood asthma
Grp78 (BiP)ATF6 and ATF4 (1) Embryonic lethality at E3.5
due to impaired embryo peri-implanta-
tion; (2) Liver deletion: simultaneous
liver damage and hepatic steatosis
(1) Adult-onset ataxia with cerebellar
Purkinje cell loss
(1) Bipolar disorder
SIL1 XBP1s (1) Marinesco-Sjogren syndrome;
(2) Alzheimer’s disease
Tyson and Stirling, 2000;
Anttonen et al., 2005;
Zhao et al., 2005,
Kakiuchi et al., 2007;
Mao et al., 2010
Grp94 XBP1s, ATF6,
(1) Embryonic lethality at E7;
(2) B cell deletion: reduced antibody
production; (3) Bone marrow deletion:
hematopoietic stem cell expansion
(1) Postnatal death; (2) Motor disorder
(1) Embryonic lethality at E14.5
(1) Disturbed redox homeostasis in the
liver and cataract development in eyes
(1) Bipolar disorder
XBP1s and ATF6
XBP1s and ATF6
XBP1s and ATF6
(1) A case of schizophrenia
(1) Inflammatory response;
(2) Non-small cell lung cancer
Ladiges et al., 2005
Denzel et al., 2002
Aghajani et al., 2006
Hart et al., 2011;
Kasaikina et al., 2011
N.A., not applicable.
on March 18, 2013
Published June 25, 2012
863 The unfolded protein response in human disease • Wang and Kaufman
states. Despite tremendous progress in understanding the physi-
ological significance of the UPR as well as the cross talk
between the UPR, metabolic, inflammatory, and other signaling
pathways, real-time analysis of protein folding in the ER and
UPR activation has only been performed in yeast (Merksamer
et al., 2008). Thus, the mechanisms involved in stimulating and
sustaining UPR signals in the pathogenesis of different diseases
is still unknown. Further studies on identifying these mechanisms
will greatly facilitate approaches to modulate UPR activity to
reach a desired therapeutic benefit.
We apologize to those who we were unable to reference due to
R.J. Kaufman is supported by National Institutes of Health grants P01
HL057346, R37 DK042394, R01 DK088227, R24 DK093074, and R01
HL052173. S. Wang is supported by postdoctoral fellowship from the American
Submitted: 31 October 2011
Accepted: 24 May 2012
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tumors. Because the UPR is highly activated in cancer cells,
chemotherapeutic agents that cause ER stress such as brefeldin A,
bortezomib (Velcade), and geldanamycin could be effective
by exacerbating UPR activation to activate apoptosis in cancer
cells (Nawrocki et al., 2005; Healy et al., 2009). Therefore,
the proapoptotic effects of the UPR may be harnessed as a
means to treat cancer.
The UPR in neurodegenerative disorders
In contrast to the indispensable role of the UPR in secretory
cells, its function in the physiology of the nervous system is not
fully understood. Studies in Xbp1-null neurons revealed that
XBP1s regulates the induction of GABAergic markers includ-
ing somatostatin, neuropeptide Y, and calbindin through brain-
derived neurotrophic factor signaling to control the neurite
extension (Hayashi et al., 2007, 2008). A polymorphism in the
XBP1 promoter was linked to a risk factor for bipolar disorder
and schizophrenia (Kakiuchi et al., 2003a). Interestingly, trans-
lational control of ATF4 mediated by GCN2–eIF2 phosphory-
lation appears important for hippocampal synaptic plasticity
and memory (Costa-Mattioli et al., 2005). Targeting inactiva-
tion of ATF4 can enhance synaptic plasticity and memory stor-
age (Chen et al., 2003). Nevertheless, the function of ATF6 and
PERK–eIF2 phosphorylation in the nervous system remains
to be determined.
Although the role of the UPR in the nervous system re-
mains speculative, activation of the UPR is observed in a num-
ber of neurodegenerative diseases including amyotrophic lateral
sclerosis, Parkinson’s disease, Huntington’s disease, prion-
related disorders, and Alzheimer’s disease, and demyelinating
neurodegenerative autoimmune diseases such as multiple scle-
rosis, Pelizaeus-Merzbacher disease, and transverse myelitis
(Doyle et al., 2011; Matus et al., 2011). Interestingly, the patho-
genic contribution of the UPR is highly specific in different dis-
ease models. Chop deletion shortened lifespan and increased
oligodendrocyte death in mice with Pelizaeus-Merzbacher
disease, whereas Chop deletion attenuated neurotoxin-induced
Parkinson’s disease (Gow and Wrabetz, 2009). In addition, de-
letion of Xbp1 delayed ALS disease onset and increased life
span due to an increase in autophagy (Hetz et al., 2009), whereas
deletion of Xbp1 did not affect neuronal loss or animal survival
in a prion-related disorder disease mouse model (Hetz and Soto,
2006). Thus, the importance of the UPR in neurodegeneration
appears disease specific, which introduces challenges to study
the functional significance of ER stress in the pathogenesis of
Although by no means exhaustive, Table 1 summarizes the
physiological functions of the UPR components in mouse mod-
els and the genetic association of these components with human
disease. The UPR contains considerable sensitivity and flexibil-
ity to exquisitely regulate ER activity and adapt cells to differ-
ent physiological conditions. As the phase of the UPR shifts
from a protective stage to proapoptotic, the UPR commits cells
to death, which can concurrently intersect with inflammatory
signaling pathways to either initiate or exacerbate pathogenic
on March 18, 2013
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Published June 25, 2012