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IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response
Jonathan H. Lin,1,2,3*
Han Li,1,2
Douglas Yasumura,4
Hannah R. Cohen,2
Chao Zhang,1,5
Barbara Panning,2
Kevan M. Shokat,1,5
Matthew M. LaVail,4
Peter Walter1,2
Abstract:
Endoplasmic reticulum (ER) stress activates a set of signalingpathways, collectively termed the unfolded protein response(UPR). The three UPR branches (IRE1, PERK, and ATF6) promotecell survival by reducing misfolded protein levels. UPR signalingalso promotes apoptotic cell death if ER stress is not alleviated.How the UPR integrates its cytoprotective and proapoptotic outputsto select between life or death cell fates is unknown. We foundthat IRE1 and ATF6 activities were attenuated by persistentER stress in human cells. By contrast, PERK signaling, includingtranslational inhibition and proapoptotic transcription regulatorChop induction, was maintained. When IRE1 activity was sustainedartificially, cell survival was enhanced, suggesting a causallink between the duration of UPR branch signaling and life ordeath cell fate after ER stress. Key findings from our studiesin cell culture were recapitulated in photoreceptors expressingmutant rhodopsin in animal models of retinitis pigmentosa.
1 Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA. 2 Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94158, USA. 3 Departments of Pathology and Ophthalmology, University of California at San Francisco, San Francisco, CA 94158, USA. 4 Departments of Anatomy and Ophthalmology, University of California at San Francisco, San Francisco, CA 94158, USA. 5 Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA 94158, USA.
* To whom correspondence should be addressed. E-mail: Jonathan.Lin{at}ucsf.edu
The UPR comprises a set of signaling pathways that collectivelyadjust the cell's ER protein folding capacity according to need.As such, UPR signaling reestablishes homeostasis in the faceof changing developmental and environmental conditions, therebypreserving ER protein folding fidelity. Upon unmitigated ERstress, the UPR also triggers apoptosis. Thus, rather than producemisfolded or malfunctioning proteins, cells are eliminated,perhaps to protect the organism from rogue cells that do notreceive or relay signals properly.
Physiologic or pathologic processes that create an imbalancebetween protein folding load and capacity induce the UPR throughER-resident transmembrane proteins—IRE1, PERK, and ATF6—thatact as sensors in the ER lumen and transmit the informationto the rest of the cell (1). IRE1 is a transmembrane kinase/endoribonuclease(RNAse) that, upon activation, initiates the nonconventionalsplicing of Xbp-1 mRNA (2, 3). Spliced Xbp-1 mRNA encodes atranscription activator that drives transcription of genes suchas ER chaperones, whose products directly participate in ERprotein folding (4). PERK is a transmembrane kinase that phosphorylatesthe eukaryotic translation initiation factor 2 subunit (eIF2),thereby reducing protein synthesis and counteracting ER proteinoverload (5). eIF2 phosphorylation also allows the selectivetranslation of some mRNAs that contain small open reading framesin their 5' untranslated regions, thereby leading to the productionof transcription activators such as ATF4 (6). ATF6 is a transcriptionfactor that is made initially as an ER-resident transmembraneprotein. Upon protein misfolding, the ATF6 cytoplasmic domain(ATF6f) is liberated from its membrane anchor by regulated proteolysis(7, 8). The transcription factors thus produced (i.e., XBP1,ATF4, and ATF6f) collaborate to activate UPR target genes, therebycontrolling the cell's response to ER stress.
Genetic studies have begun to assign cytoprotective or proapoptoticfunctions to individual UPR target genes. For instance, expressionof the ER chaperone BiP protects cells from ER stress (9), whereasCHOP, a B-ZIP transcription factor induced by the PERK branchof the UPR, promotes cell death (10). Paradoxically, all knownER stresses simultaneously elicit protective and toxic outputsfrom the UPR, and it has remained unclear how the UPR integratesthese opposing outputs to arrive at a life or death decision.
IRE1 signaling is attenuated during persistent ER stress. Todetermine the activation status of IRE1 after ER stress, weexamined Xbp-1 mRNA splicing by reverse transcription polymerasechain reaction (RT-PCR) in human embryonic kidney (HEK) 293cells (Fig. 1A). We observed the appearance of spliced Xbp-1mRNA after treating the cells with tunicamycin or thapsigargin:agents that elicit ER stress by blocking N-linked glycosylationor inhibiting the ER Ca2+ pump, respectively (Fig. 1B). Unexpectedly,we found a strong diminution in Xbp-1 mRNA splicing with prolongedexposure to either drug (Fig. 1B). Consistent with the mRNAsplicing data, XBP-1s protein levels (the form of XBP-1 derivedfrom its spliced mRNA) also decreased with prolonged drug treatment(Fig. 1B). Other human cell lines showed qualitatively similareffects, although they differed in the observed timing of onsetand shutoff, as well as in the degree of Xbp-1 mRNA splicing(fig. S1).
Fig. 1.. Kinetics of IRE1 signaling with persistent ER stress. (A) WT Ire1+/+ or Ire1–/– mouse embryo fibroblasts were treated with tunicamycin (tm) (5 µg/ml), and Xbp-1 mRNA splicing was determined by RT-PCR. Unspliced (u) and spliced (s) Xbp-1 mRNA products are indicated. The asterisk indicates the position of a hybrid amplicon (27). XBP-1s was detected by immunoblotting. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels served as a protein loading control. (B) HEK293 cells were treated with tm (5 µg/ml) or thapsigargin (tg) (500 nM) for the indicated times. tm, red bars; tg, blue bars. Results are representative of five independent experiments. (C) HEK293 cells were treated with agents for the indicated times. At 24 hours, media containing drug were transferred to fresh cells. After 4 additional hours, Xbp-1 mRNA splicing was determined by RT-PCR. (D) HEK293 cells, transfected with VCAM-1, were treated with tm (5 µg/ml) for the indicated times. Xbp-1 mRNA splicing was determined by RT-PCR. Mature and deglycosylated (dg) VCAM-1 species were determined by immunoblotting. (E) HEK293 cells, transfected with VCAM-1, were treated with tm for the indicated times and were pulse-labeled, and radiolabeled VCAM-1 was detected after immunoprecipitation. The double asterisk indicates the position of a nonspecific band used as a loading control. (F) HEK293 cells were treated with tg for the indicated times, and phospho-JNK protein levels were assessed by immunoblotting. Total JNK protein levels served as a loading control.
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To ascertain that loss of Xbp-1 mRNA splicing at the late timepoints was not due to inactivation of the ER stress–inducingagents, we transferred media from HEK293 cells that had beentreated with tunicamycin or thapsigargin for 24 hours (a timewhen little Xbp-1 mRNA splicing was seen) to plates of fresh,untreated cells. After 4 hours of incubation in conditionedmedia, Xbp-1 mRNA splicing was induced to a degree indistinguishableto that seen in cells treated with fresh agents (Fig. 1C).
We next tested if, at late time points, cells continued to accumulatemisfolded proteins in their ER or had acquired means of neutralizingthe effects of the ER stress–inducing agents. To thisend, we examined the glycosylation status of vascular cell adhesionmolecule–1 (VCAM-1), a transmembrane protein that is cotranslationallyinserted into the ER membrane where it becomes N-glycosylated(11). We transfected HEK293 cells with VCAM-1, added tunicamycin,and compared IRE1 activity with the glycosylation status ofVCAM-1 (Fig. 1D). HEK293 cells expressing VCAM-1 spliced Xbp-1mRNA in a manner indistinguishable from that of wild-type (WT)cells after tunicamycin treatment, and, as in untransfectedcells, Xbp-1 mRNA splicing progressively decayed back to baselinelevels with prolonged treatment (Fig. 1D). VCAM-1 was fullyglycosylated before tunicamycin addition and first became partiallyglycosylated and then unglycosylated (Fig. 1D). Not only thesteady-state pool but also all newly synthesized VCAM-1 wasunglycosylated at later time points (Fig. 1E).
To determine if other IRE1-dependent functions were attenuatedin a manner akin to Xbp-1 mRNA splicing, we examined the activationstatus of c-Jun N-terminal kinase (JNK). In response to ER stress,IRE1 initiates a signal transduction pathway that activatesJNK (12). In HEK293 cells, JNK was rapidly phosphorylated withER stress (Fig. 1F). The initial burst in phosphorylation wasfollowed by a progressive decrease in phospho-JNK levels, atrend that paralleled Xbp-1 mRNA splicing (compare the timepoints from 4 hours to 20 hours in Fig. 1F with the equivalenttime points in Fig. 1B). Thus, cells responded to unmitigatedER stress by first activating and then attenuating IRE1 activity.
Behavior of ATF6 and PERK signaling with persistent ER stress.To assess whether other branches of the UPR elicit kinetic behaviorsimilar to that elicited by IRE1, we monitored ATF6 and PERKactivities over time (after UPR induction). To measure ATF6activation, we followed the liberation of its cleaved cytosolicfragment, ATF6f, using a FLAG-tagged ATF6 reporter that recapitulatedATF6 processing upon induction of ER stress (13). We saw rapidproduction of ATF6f after exposure of HEK293 cells to ER stress(Fig. 2A). With prolonged ER stress, ATF6f levels diminishedand ultimately disappeared (Fig. 2A). Thus, like IRE1 signaling,ATF6 activation also diminished after prolonged ER stress, albeitwith different kinetics: Although IRE1 signaling decayed within8 hours, cessation of ATF6f production was not apparent untilafter at least 20 hours of continuous stress.
Fig. 2.. Kinetics of ATF6 and PERK with persistent ER stress. (A) HEK293 cells, expressing FLAG-tagged ATF6, were treated with tg (500 nM) for the indicated times, and ATF6f was detected by immunoblotting. GAPDH levels served as a protein loading control. (B) HEK293 cells were treated with tg, and phospho-PERK, phospho-eIF2, and ATF-4 levels were determined by immunoblotting. Total eIF2 levels served as a protein loading control. In the bottom panels, cells were treated with drug for the indicated times and were pulse-labeled, and radioisotope incorporation was measured via phosphoimaging. 35S-Met/Cys, 35S-labeled methionine/cysteine. (C) Cells were treated with agents (tm, red bars; tg, blue bars) for the indicated hours, and normalized BiP (top panel) and Chop (bottom panel) mRNA levels were measured by quantitative PCR and shown relative to levels in untreated cells. Error bars represent SDs from five independent experiments.
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The dynamics of the transcriptional targets of IRE1 and ATF6were consistent with the induction kinetics of these ER-proximalUPR signal transducers. Induction of BiP mRNA, encoding an HSP70-classER chaperone that is transcriptionally regulated by both ATF6fand XBP-1s (4, 7), peaked at 8 hours after drug treatment andthen declined to near preinduction levels (Fig. 2C).
To assess the activation kinetics of the PERK branch of theUPR, we monitored the accumulation of phosphorylated PERK andits downstream product: phosphorylated eIF2. PERK activationdid not diminish even after prolonged ER stress (Fig. 2B). Consistentwith this finding, the translational capacity of cells remainedattenuated at all times after the imposition of ER stress (Fig. 2B).Similarly, we observed continuous production of ATF4 (Fig. 2B)and its transcriptional target Chop after ER stress (Fig. 2C),although there was some gradual diminution at the later timepoints. Thus, by contrast to IRE1 and ATF6, PERK branch activationis largely sustained with unmitigated ER stress.
Chemical-genetic control of IRE1 signaling in human cells. Toask whether the attenuation of IRE1 activity had physiologicalconsequences, we sought to selectively control IRE1 activity.We followed a strategy that permitted chemical regulation ofIRE1's RNase activity using the adenosine triphosphate (ATP)analog 4-amino-1-tert-butyl-3-(1'-naphthylmethyl)pyrazolo[3,4-d]pyrimidine (1NM-PP1) (Fig. 3A), which binds selectively to thekinase domain of IRE1 mutants bearing an enlarged ATP-bindingsite (14). A leucine-to-glycine [Leu745Gly745 (L745G)] mutationrendered yeast IRE1 sensitive to 1NM-PP1. We therefore constructedan allele of human IRE1 in which the orthologous amino acid[isoleucine 642 (Ile642)] was changed to glycine [Fig. 3A, "IRE1(I642G)"].Because conventional transfection or transduction gene expressionactivated the UPR constitutively and caused cell death (15,16), we used flippase-mediated, site-specific DNA recombinationto introduce the drug-sensitized IRE1(I642G) mutant allele directlyinto the genome of HEK293 cells bearing a defined frt site (17).No deleterious growth defects were observed in the transgeniccells expressing the IRE1(I642G) allele. The UPR was not constitutivelyinduced in these cells, as indicated by the absence of splicedXbp-1 mRNA (Fig. 3B, 0-hours time point). Application of 1NM-PP1alone induced robust splicing of Xbp-1 mRNA in IRE1(I642G)-expressingcells but had no effect on Xbp-1 mRNA in the parental cells(Fig. 3B). By contrast, the corresponding 1NM-PP1–sensitizedallele in yeast required both ER protein misfolding and 1NM-PP1to activate HAC1 mRNA splicing. The human allele, thus, provideda molecular switch that could be toggled by 1NM-PP1 regardlessof ER protein folding status.
Fig. 3.. Chemical-genetic control of human IRE1. (A) Alignments of a portion of the ATP-binding domains of yeast and human IRE1 are shown. The residue mutated to glycine is shown in color (28). The structure of the ATP analog, 1NM-PP1, is shown below. (B) Parental WT and transgenic HEK293 cells expressing 1NM-PP1–sensitized IRE1 were treated for the indicated times with 1NM-PP1 (5 µM), and Xbp-1 mRNA splicing was determined by RT-PCR. (C) Transgenic HEK293 cells were treated with tm (5 µg/ml) ± 1NM-PP1 (5 µM). Xbp-1 mRNA splicing was assessed by RT-PCR and quantified. Results are representative of five independent experiments. (D) Transgenic HEK293 cells were treated with tg (300 nM) ± 1NM-PP1 (5 µM). Xbp-1 mRNA splicing was assessed by RT-PCR and quantified. Results are representative of five independent experiments.
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We used IRE1(I642G)-expressing cells to test if we could manipulateXbp-1 mRNA splicing during prolonged ER stress. As in WT cells,in the absence of 1NM-PP1, robust Xbp-1 mRNA splicing occurredin the transgenic cells after drug treatment at early time pointsand then diminished at later time points (Fig. 3, C and D; comparetop panels to Fig. 1A). Thus, the expression of the mutant allelehad no deleterious effects on IRE1 activation or attenuationby prolonged ER stress. By contrast, in the presence of 1NM-PP1,Xbp-1 mRNA splicing in transgenic cells was induced and remainedelevated (Fig. 3, C and D). Thus, artificial activation of IRE1(I642G)by 1NM-PP1 overcame the attenuation of IRE1 activity seen uponprolonged ER stress, sustaining Xbp-1 mRNA splicing at levelsapproaching those seen at early time points (Fig. 3, C and D,bottom panels). Although 1NM-PP1 activated IRE1(I642G)'s RNAseactivity, we detected no comparable activation of JNK signaling(fig. S2), indicating that the mRNA splicing function of IRE1(I642G)is selectively activated by 1NM-PP1.
IRE1 activity enhances cell viability. 1NM-PP1 control of IRE1allowed us to assess the physiological consequences of IRE1activation and attenuation during the UPR. In particular, weasked whether extended IRE1 activation would have a beneficialeffect on cell viability upon prolonged ER stress. ER stressinduced by both tunicamycin and thapsigargin is toxic to HEK293cells. Forty-eight hours after treatment, less than 2% of theWT cells survived (Fig. 4 and fig. S3). The addition of 1NM-PP1had no substantial effect, although it diminished the viabilityof WT cells slightly (25% reduction in viable cell number).
Fig. 4.. IRE1 signaling enhances cell viability. Parental WT and transgenic HEK293 cells were treated with the indicated agents, and adherent, cresyl violet–stained positive cells were counted at the indicated times and are shown relative to counts of mock-treated cells. Error bars represent SDs from three independent experiments. The arrows indicate P value < 0.01 when the corresponding samples ± 1NM-PP1 were compared (Student's t test).
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By contrast, 1NM-PP1 treatment of HEK293 cells expressing IRE1(I642G)significantly improved their survival. At the 48-hours timepoint, cell numbers after thapsigargin and tunicamycin treatmentwere 5 and 20 times higher, respectively, in the presence of1NM-PP1 than in its absence (Fig. 4). Even in the absence ofexperimental induction of ER stress, 1NM-PP1 proved beneficialin cells expressing IRE1(I642G), affording a 30% enhancementof cell growth (Fig. 4 and fig. S3). Thus, IRE1 signaling directlyenhanced cell viability in the face of ER stress.
UPR behavior in models of retinitis pigmentosa. The UPR hasbeen postulated to play a role in the pathogenesis of proteinmisfolding diseases (18). Autosomal dominant retinitis pigmentosa(adRP) is a human protein misfolding disease most commonly causedby a proline-to-histidine mutation at position 23 of rhodopsin(P23H rhodopsin) that leads to its retention within the ER (19–21).Retinal photoreceptors expressing P23H rhodopsin ultimatelydie, leading to blindness, but the molecular pathways linkingrhodopsin misfolding in the ER to cell death are unclear (22).To explore whether the UPR is instrumental in retinal cell death,we examined its activation status in cells expressing P23H rhodopsin.
We assessed P23H rhodopsin's ability to induce ER stress intransfected HEK293 cells. Increased BiP mRNA levels were detectedin cells expressing two control ER-targeted proteins, VCAM-1and WT rhodopsin (Fig. 5A), but not in cells expressing cytosolicgreen fluorescent protein (GFP), indicating that increasingthe protein folding load of the ER induced the UPR. BiP mRNAexpression was significantly higher in cells expressing P23Hrhodopsin as compared with cells expressing WT rhodopsin (Fig. 5A).The rhodopsin mRNA levels were identical in cells expressingWT and mutant forms of the protein. Thus, P23H rhodopsin isa more potent UPR inducer than WT rhodopsin, presumably becauseof its folding defect.
Fig. 5..BiP and Chop expression in animals expressing P23H rhodopsin. (A) HEK293 cells were transfected as indicated, and normalized BiP mRNA levels were measured by quantitative PCR and are shown relative to levels in untreated cells. Values represent the means ± SDs from five independent experiments. (B) Normalized BiP and Chop mRNA levels were measured in retinas [from WT Sprague-Dawley or transgenic rats expressing P23H rhodopsin at high (P23H-1 Rho Tg) or low (P23H-3 Rho Tg) levels] by quantitative PCR and are shown relative to levels at PND 6 (P6): a time when >95% of the mature complement of retinal photoreceptors has been generated. Error bars represent SDs from three animals at each age. *, P = 0.003; **, P < 0.001 [as compared with age-matched WT animals (Student's t test)]. (C) Light micrographs of representative retinal sections from the inferior posterior retinas of WT, P23H-1, and P23H-3 rats at the indicated ages. The outer nuclear layer (ONL), which is proportional to photoreceptor nuclei numbers, thins as photoreceptors degenerate, and rhodopsin-containing outer segments (arrowheads) shorten. Scale bar, 25 µm. (D) The mean ONL thickness was measured in retinal cross sections from transgenic and WT rats at the indicated ages. Error bars represent SDs of ONL thickness from three to six animals at each age. The onset of ONL thinning in both transgenes was at P12 (P < 0.05), with progressive thinning at later ages (P < 0.0001) (Student's t test).
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We next examined BiP and Chop mRNA levels in retinas from transgenicrat models of adRP that express mouse P23H rhodopsin at low(P23H-3 Rho Tg) or high (P23H-1 Rho Tg) levels (23, 24). InWT Sprague-Dawley rats and those expressing the P23H rhodopsintransgene at either level, BiP mRNA increased after the birthof photoreceptor neurons [postnatal day 6 (PND 6)] and increasedup to PND 10 or 12 (Fig. 5B). Thereafter, BiP mRNA levels selectivelydropped in both transgenic lines expressing P23H rhodopsin (Fig. 5B,top panel). By contrast, Chop mRNA levels concomitantly increasedin animals expressing P23H rhodopsin but remained low in WTanimals (Fig. 5B, bottom panel). The time course of BiP mRNAdecline and Chop mRNA rise tightly matched the rate of retinaldegeneration in P23H rhodopsin transgenic animals (Fig. 5, C and D).Furthermore, the changes in BiP and Chop mRNA levels in retinasexpressing misfolded rhodopsin mirrored the results seen incell culture after prolonged ER stress (compare Figs. 5B and2C). Thus, selective attenuation of cytoprotective UPR outputcoupled with sustained CHOP production—seen after drug-inducedprotein misfolding in vitro or, in the case of P23H rhodopsin,constitutive misfolded protein production in vivo—contributedto cell death.
Discussion. The UPR elicits paradoxical outputs, inducing cytoprotectivefunctions that reestablish homeostasis and cell destructivefunctions that promote apoptosis. We found that the switch betweencytoprotective and proapoptotic output lies in part in the durationof individual UPR branch activity. After rapid initial activationof all UPR branches by ER stress, IRE1 signaling was selectivelyattenuated in human cells, even though stress persisted. ATF6signaling also declined with slower kinetics, yet PERK signalingpersisted much longer in the presence of unmitigated ER stress.We observed enhanced cell survival after experimentally prolongingIRE1 signaling, thereby demonstrating a causal link betweenIRE1 activity and cell survival. Thus, IRE1 signaling attenuationby persistent ER stress emerges as a key step in making thelife or death decision after UPR induction.
Our results suggest a model by which distinct combinations ofindividual UPR signaling pathways determine a cell's fate afterER stress. The initial combined activation of IRE1, PERK, andATF6 produces cytoprotective outputs such as reduced translation,enhanced ER protein folding capacity, and clearance of misfoldedER proteins, along with proapoptotic outputs such as CHOP production.Cytoprotective outputs would outweigh proapoptotic factors atthis point, which would be helped by the relatively longer mRNAand protein half-lives of factors such as BiP (25). This phaseof predominantly beneficial UPR output would thus provide a"window of opportunity" for cells to readjust their ER to copewith stress. If these steps fail to reestablish homeostasis,IRE1 signaling and then ATF6 signaling are attenuated, creatingan imbalance in which unchecked proapoptotic output guides thecell toward its demise. The variation in IRE1 signaling kineticsacross different human cell types (fig. S1) may reflect differentialsusceptibility to ER stress–induced cell death among differentcells and organs, reinforcing growing evidence that the metazoanUPR is tailored toward the physiologic functions of particularorgans and cell types (26).
The experimental conditions used in our cell culture studiesinduce irreparable protein misfolding and resemble pathologicalprocesses in which inherited mutations produce misfolded proteins.It was unexpected that in retinal degeneration models, rhodopsinmolecules bearing the causative mutation of the disease inducedchanges in UPR activity that resembled those observed with unmitigatedstress after drug treatment. Whereas WT retinal cells inducedBiP concomitant with the developmental need to fold large amountsof rhodopsin, retinal cells expressing mutant rhodopsin selectivelyshut down BiP production and increased CHOP production, suggestingthat down-regulation of IRE1, coupled with maintenance of PERKsignaling, may drive the cell death seen with the P23H rhodopsinmutation. Similarly, insufficient or imbalanced UPR output couldalso trigger cell loss in other diseases that arise from persistentER stress.
Single-letter abbreviations for the amino acid residues areas follows: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; and Y, Tyr.
We thank the Walter lab, B. Farese, J. L. Garrison, R. J. Kaufman, R. Locksley, M. Matthes, D. Morgan, J. Nathans, R. Prywes, F. Sanchez, and B. Yen for comments, provision of reagents, or technical advice. This work was supported by the Amyotrophic Lateral Sclerosis Association, U.S. Department of Defense, Foundation Fighting Blindness, John Douglas French Alzheimer's Foundation, National Eye Institute, NIH, and Research to Prevent Blindness. P.W. and K.M.S. are Howard Hughes Medical Institute Investigators.
Received for publication 12 June 2007. Accepted for publication 7 September 2007.
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S. Kahali, B. Sarcar, A. Prabhu, E. Seto, and P. Chinnaiyan (2012)
FASEB J
26, 2437-2445
|Abstract »|Full Text »|PDF »
New Insights into Translational Regulation in the Endoplasmic Reticulum Unfolded Protein Response.
Endoplasmic Reticulum Stress in Retinal Vascular Degeneration: Protective Role of Resveratrol.
C. Li, L. Wang, K. Huang, and L. Zheng (2012)
Invest. Ophthalmol. Vis. Sci.
53, 3241-3249
|Abstract »|Full Text »|PDF »
Regulation of Subtilase Cytotoxin-Induced Cell Death by an RNA-Dependent Protein Kinase-Like Endoplasmic Reticulum Kinase-Dependent Proteasome Pathway in HeLa Cells.
K. Yahiro, H. Tsutsuki, K. Ogura, S. Nagasawa, J. Moss, and M. Noda (2012)
Infect. Immun.
80, 1803-1814
|Abstract »|Full Text »|PDF »
Disturbance of Ca2+ Homeostasis Converts Pro-Met into Non-canonical Tyrosine Kinase p190MetNC in Response to Endoplasmic Reticulum Stress in MHCC97 Cells.
R. Dai, J. Li, J. Fu, Y. Chen, L. Yu, X. Zhao, Y. Qian, H. Zhang, H. Chen, Y. Ren, et al. (2012)
J. Biol. Chem.
287, 14586-14597
|Abstract »|Full Text »|PDF »
The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology.
Endoplasmic Reticulum Stress, the Unfolded Protein Response, Autophagy, and the Integrated Regulation of Breast Cancer Cell Fate.
R. Clarke, K. L. Cook, R. Hu, C. O. B. Facey, I. Tavassoly, J. L. Schwartz, W. T. Baumann, J. J. Tyson, J. Xuan, Y. Wang, et al. (2012)
Cancer Res.
72, 1321-1331
|Abstract »|Full Text »|PDF »
IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin.
Mislocalization and Degradation of Human P23H-Rhodopsin-GFP in a Knockin Mouse Model of Retinitis Pigmentosa.
B. A. Price, I. M. Sandoval, F. Chan, D. L. Simons, S. M. Wu, T. G. Wensel, and J. H. Wilson (2011)
Invest. Ophthalmol. Vis. Sci.
52, 9728-9736
|Abstract »|Full Text »|PDF »
Crosstalk Between Endoplasmic Reticulum Stress and Mitochondrial Pathway Mediates Cadmium-Induced Germ Cell Apoptosis in Testes.
Y.-L. Ji, H. Wang, X.-F. Zhao, Q. Wang, C. Zhang, Y. Zhang, M. Zhao, Y.-H. Chen, X.-H. Meng, and D.-X. Xu (2011)
Toxicol. Sci.
124, 446-459
|Abstract »|Full Text »|PDF »
Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease.
C. L. Gentile, A. M. Nivala, J. C. Gonzales, K. T. Pfaffenbach, D. Wang, Y. Wei, H. Jiang, D. J. Orlicky, D. R. Petersen, M. J. Pagliassotti, et al. (2011)
Am J Physiol Regulatory Integrative Comp Physiol
301, R1710-R1722
|Abstract »|Full Text »|PDF »
The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation.
The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress.
B. F. Teske, S. A. Wek, P. Bunpo, J. K. Cundiff, J. N. McClintick, T. G. Anthony, and R. C. Wek (2011)
Mol. Biol. Cell
22, 4390-4405
|Abstract »|Full Text »|PDF »
Protein Misfolding and Retinal Degeneration.
R. Tzekov, L. Stein, and S. Kaushal (2011)
Cold Spring Harb Perspect Biol
3, a007492
|Abstract »|Full Text »|PDF »
The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1{alpha}.
C. Hetz, F. Martinon, D. Rodriguez, and L. H. Glimcher (2011)
Physiol Rev
91, 1219-1243
|Abstract »|Full Text »|PDF »
Prevention of Doxorubicin Cardiopathic Changes by a Benzyl Styryl Sulfone in Mice.
M. Lu, S. Merali, R. Gordon, J. Jiang, Y. Li, J. Mandeli, X. Duan, J. Fallon, and J. F. Holland (2011)
Genes & Cancer
2, 985-992
|Abstract »|Full Text »|PDF »
The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury.
E. Mantuano, K. Henry, T. Yamauchi, N. Hiramatsu, K. Yamauchi, S. Orita, K. Takahashi, J. H. Lin, S. L. Gonias, and W. M. Campana (2011)
J. Neurosci.
31, 13376-13385
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Heightened Induction of Proapoptotic Signals in Response to Endoplasmic Reticulum Stress in Primary Fibroblasts from a Mouse Model of Longevity.
A. A. Sadighi Akha, J. M. Harper, A. B. Salmon, B. A. Schroeder, H. M. Tyra, D. T. Rutkowski, and R. A. Miller (2011)
J. Biol. Chem.
286, 30344-30351
|Abstract »|Full Text »|PDF »
The Cytosolic Chaperone Hsc70 Promotes Traffic to the Cell Surface of Intracellular Retained Melanocortin-4 Receptor Mutants.
E. Meimaridou, S. B. Gooljar, N. Ramnarace, L. Anthonypillai, A. J. L. Clark, and J. P. Chapple (2011)
Mol. Endocrinol.
25, 1650-1660
|Abstract »|Full Text »|PDF »
Peptides derived from the bifunctional kinase/RNase enzyme IRE1{alpha} modulate IRE1{alpha} activity and protect cells from endoplasmic reticulum stress.
M. Bouchecareilh, A. Higa, S. Fribourg, M. Moenner, and E. Chevet (2011)
FASEB J
25, 3115-3129
|Abstract »|Full Text »|PDF »
Treatment-Induced Oxidative Stress and Cellular Antioxidant Capacity Determine Response to Bortezomib in Mantle Cell Lymphoma.
M. A. Weniger, E. G. Rizzatti, P. Perez-Galan, D. Liu, Q. Wang, P. J. Munson, N. Raghavachari, T. White, M. M. Tweito, K. Dunleavy, et al. (2011)
Clin. Cancer Res.
17, 5101-5112
|Abstract »|Full Text »|PDF »
Endoplasmic-Reticulum Calcium Depletion and Disease.
D. Mekahli, G. Bultynck, J. B. Parys, H. De Smedt, and L. Missiaen (2011)
Cold Spring Harb Perspect Biol
3, a004317
|Abstract »|Full Text »|PDF »
A reporter for tracking the UPR in vivo reveals patterns of temporal and cellular stress during atherosclerotic progression.
E. Thorp, T. Iwawaki, M. Miura, and I. Tabas (2011)
J. Lipid Res.
52, 1033-1038
|Abstract »|Full Text »|PDF »
Heat induces the splicing by IRE1 of a mRNA encoding a transcription factor involved in the unfolded protein response in Arabidopsis.
Y. Deng, S. Humbert, J.-X. Liu, R. Srivastava, S. J. Rothstein, and S. H. Howell (2011)
PNAS
108, 7247-7252
|Abstract »|Full Text »|PDF »
Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability.
Y. Liu, S. Y. Lee, E. Neely, W. Nandar, M. Moyo, Z. Simmons, and J. R. Connor (2011)
J. Biol. Chem.
286, 13161-13170
|Abstract »|Full Text »|PDF »
Loss of Subcellular Lipid Transport Due to ARV1 Deficiency Disrupts Organelle Homeostasis and Activates the Unfolded Protein Response.
C. F. Shechtman, A. L. Henneberry, T. A. Seimon, A. H. Tinkelenberg, L. J. Wilcox, E. Lee, M. Fazlollahi, A. B. Munkacsi, H. J. Bussemaker, I. Tabas, et al. (2011)
J. Biol. Chem.
286, 11951-11959
|Abstract »|Full Text »|PDF »
Attenuation of yeast UPR is essential for survival and is mediated by IRE1 kinase.
A. Chawla, S. Chakrabarti, G. Ghosh, and M. Niwa (2011)
J. Cell Biol.
193, 41-50
|Abstract »|Full Text »|PDF »
Activation of Unfolded Protein Response in Transgenic Mouse Lenses.
L. W. Reneker, H. Chen, and P. A. Overbeek (2011)
Invest. Ophthalmol. Vis. Sci.
52, 2100-2108
|Abstract »|Full Text »|PDF »
Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations.
S. Sakami, T. Maeda, G. Bereta, K. Okano, M. Golczak, A. Sumaroka, A. J. Roman, A. V. Cideciyan, S. G. Jacobson, and K. Palczewski (2011)
J. Biol. Chem.
286, 10551-10567
|Abstract »|Full Text »|PDF »
A CHOP-regulated microRNA controls rhodopsin expression.
S. Behrman, D. Acosta-Alvear, and P. Walter (2011)
J. Cell Biol.
192, 919-927
|Abstract »|Full Text »|PDF »
PKR-dependent CHOP induction limits hyperoxia-induced lung injury.
T. I. Lozon, A. J. Eastman, G. Matute-Bello, P. Chen, T. S. Hallstrand, and W. A. Altemeier (2011)
Am J Physiol Lung Cell Mol Physiol
300, L422-L429
|Abstract »|Full Text »|PDF »
Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response.
A. Burkart, X. Shi, M. Chouinard, and S. Corvera (2011)
J. Biol. Chem.
286, 4081-4089
|Abstract »|Full Text »|PDF »
Preconditioning with Endoplasmic Reticulum Stress Mitigates Retinal Endothelial Inflammation via Activation of X-box Binding Protein 1.
The Proprotein Convertase PC7: UNIQUE ZYMOGEN ACTIVATION AND TRAFFICKING PATHWAYS.
E. Rousselet, S. Benjannet, J. Hamelin, M. Canuel, and N. G. Seidah (2011)
J. Biol. Chem.
286, 2728-2738
|Abstract »|Full Text »|PDF »
Bifunctional Apoptosis Regulator (BAR), an Endoplasmic Reticulum (ER)-associated E3 Ubiquitin Ligase, Modulates BI-1 Protein Stability and Function in ER Stress.
J. Rong, L. Chen, J. I. Toth, M. Tcherpakov, M. D. Petroski, and J. C. Reed (2011)
J. Biol. Chem.
286, 1453-1463
|Abstract »|Full Text »|PDF »
Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4-CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA.
Z. Galehdar, P. Swan, B. Fuerth, S. M. Callaghan, D. S. Park, and S. P. Cregan (2010)
J. Neurosci.
30, 16938-16948
|Abstract »|Full Text »|PDF »
Melanoma Differentiation Associated Gene-7/Interleukin-24 Potently Induces Apoptosis in Human Myeloid Leukemia Cells through a Process Regulated by Endoplasmic Reticulum Stress.
M. Rahmani, M. Mayo, R. Dash, U. K. Sokhi, I. P. Dmitriev, D. Sarkar, P. Dent, D. T. Curiel, P. B. Fisher, and S. Grant (2010)
Mol. Pharmacol.
78, 1096-1104
|Abstract »|Full Text »|PDF »
Human Immunodeficiency Virus-1 Tat Activates Calpain Proteases via the Ryanodine Receptor to Enhance Surface Dopamine Transporter Levels and Increase Transporter-Specific Uptake and Vmax.
S. W. Perry, J. Barbieri, N. Tong, O. Polesskaya, S. Pudasaini, A. Stout, R. Lu, M. Kiebala, S. B. Maggirwar, and H. A. Gelbard (2010)
J. Neurosci.
30, 14153-14164
|Abstract »|Full Text »|PDF »
The Role of Endoplasmic Reticulum Stress in the Progression of Atherosclerosis.
Role of CAAT/Enhancer Binding Protein Homologous Protein in Panobinostat-Mediated Potentiation of Bortezomib-Induced Lethal Endoplasmic Reticulum Stress in Mantle Cell Lymphoma Cells.
R. Rao, S. Nalluri, W. Fiskus, A. Savoie, K. M. Buckley, K. Ha, R. Balusu, A. Joshi, V. Coothankandaswamy, J. Tao, et al. (2010)
Clin. Cancer Res.
16, 4742-4754
|Abstract »|Full Text »|PDF »
Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering.
H. Li, A. V. Korennykh, S. L. Behrman, and P. Walter (2010)
PNAS
107, 16113-16118
|Abstract »|Full Text »|PDF »
Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells.
M. Baou, S. L. Kohlhaas, M. Butterworth, M. Vogler, D. Dinsdale, R. Walewska, A. Majid, E. Eldering, M. J. S. Dyer, and G. M. Cohen (2010)
Haematologica
95, 1510-1518
|Abstract »|Full Text »|PDF »
Endoplasmic Reticulum Protein Quality Control and Its Relationship to Environmental Stress Responses in Plants.
In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences.
K. Y. Tsang, D. Chan, J. F. Bateman, and K. S. E. Cheah (2010)
J. Cell Sci.
123, 2145-2154
|Abstract »|Full Text »|PDF »
Autophagy Induction by Capsaicin in Malignant Human Breast Cells Is Modulated by p38 and Extracellular Signal-Regulated Mitogen-Activated Protein Kinases and Retards Cell Death by Suppressing Endoplasmic Reticulum Stress-Mediated Apoptosis.
The Activity of Yeast Hog1 MAPK Is Required during Endoplasmic Reticulum Stress Induced by Tunicamycin Exposure.
F. Torres-Quiroz, S. Garcia-Marques, R. Coria, F. Randez-Gil, and J. A. Prieto (2010)
J. Biol. Chem.
285, 20088-20096
|Abstract »|Full Text »|PDF »
Late Phase of the Endoplasmic Reticulum Stress Response Pathway Is Regulated by Hog1 MAP Kinase.
A. A. Bicknell, J. Tourtellotte, and M. Niwa (2010)
J. Biol. Chem.
285, 17545-17555
|Abstract »|Full Text »|PDF »
ER stress and the unfolded protein response in intestinal inflammation.
M. A. McGuckin, R. D. Eri, I. Das, R. Lourie, and T. H. Florin (2010)
Am J Physiol Gastrointest Liver Physiol
298, G820-G832
|Abstract »|Full Text »|PDF »
Regulation of basal cellular physiology by the homeostatic unfolded protein response.
AlphaScreen(R)-Based Characterization of the Bifunctional Kinase/RNase IRE1{alpha}: A Novel and Atypical Drug Target.
M. Bouchecareilh, M. E. Caruso, P. Roby, S. Parent, N. Rouleau, S. Taouji, O. Pluquet, R. Bosse, M. Moenner, and E. Chevet (2010)
J Biomol Screen
15, 406-417
|Abstract »|Full Text »|PDF »
Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells.
R. Rao, S. Nalluri, R. Kolhe, Y. Yang, W. Fiskus, J. Chen, K. Ha, K. M. Buckley, R. Balusu, V. Coothankandaswamy, et al. (2010)
Mol. Cancer Ther.
9, 942-952
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Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78.
M. S. Gorbatyuk, T. Knox, M. M. LaVail, O. S. Gorbatyuk, S. M. Noorwez, W. W. Hauswirth, J. H. Lin, N. Muzyczka, and A. S. Lewin (2010)
PNAS
107, 5961-5966
|Abstract »|Full Text »|PDF »
Chimeric tRNAs as tools to induce proteome damage and identify components of stress responses.
R. Geslain, L. Cubells, T. Bori-Sanz, R. Alvarez-Medina, D. Rossell, E. Marti, and L. R. de Pouplana (2010)
Nucleic Acids Res.
38, e30
|Abstract »|Full Text »|PDF »
Alisol B, a Novel Inhibitor of the Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPase Pump, Induces Autophagy, Endoplasmic Reticulum Stress, and Apoptosis.
B. Y. K. Law, M. Wang, D.-L. Ma, F. Al-Mousa, F. Michelangeli, S.-H. Cheng, M. H. L. Ng, K.-F. To, A. Y. F. Mok, R. Y. Y. Ko, et al. (2010)
Mol. Cancer Ther.
9, 718-730
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Regulation of Endoplasmic Reticulum Stress-induced Cell Death by ATF4 in Neuroectodermal Tumor Cells.
J. L. Armstrong, R. Flockhart, G. J. Veal, P. E. Lovat, and C. P. F. Redfern (2010)
J. Biol. Chem.
285, 6091-6100
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ER Stress in Pancreatic {beta} Cells: The Thin Red Line Between Adaptation and Failure.
Severe Retinal Degeneration Caused by a Novel Rhodopsin Mutation.
H. Liu, M. Wang, C.-H. Xia, X. Du, J. G. Flannery, K. D. Ridge, B. Beutler, and X. Gong (2010)
Invest. Ophthalmol. Vis. Sci.
51, 1059-1065
|Abstract »|Full Text »|PDF »
A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1{alpha} Activation in Pancreatic {beta} Cells.
Y. Qiu, T. Mao, Y. Zhang, M. Shao, J. You, Q. Ding, Y. Chen, D. Wu, D. Xie, X. Lin, et al. (2010)
Science Signaling
3, ra7
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The flavoheme reductase Ncb5or protects cells against endoplasmic reticulum stress-induced lipotoxicity.
Y. Zhang, K. Larade, Z.-g. Jiang, S. Ito, W. Wang, H. Zhu, and H. F. Bunn (2010)
J. Lipid Res.
51, 53-62
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The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress.
G. Cantero-Recasens, C. Fandos, F. Rubio-Moscardo, M. A. Valverde, and R. Vicente (2010)
Hum. Mol. Genet.
19, 111-121
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A dual role for EDEM1 in the processing of rod opsin.
M. Kosmaoglou, N. Kanuga, M. Aguila, P. Garriga, and M. E. Cheetham (2009)
J. Cell Sci.
122, 4465-4472
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Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein.
Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton.
C. M. Massaro, J. Pielage, and G. W. Davis (2009)
J. Cell Biol.
187, 101-117
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Regulated Ire1-dependent decay of messenger RNAs in mammalian cells.
J. Hollien, J. H. Lin, H. Li, N. Stevens, P. Walter, and J. S. Weissman (2009)
J. Cell Biol.
186, 323-331
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Induction of endoplasmic reticulum stress response by TZD18, a novel dual ligand for peroxisome proliferator-activated receptor {alpha}/{gamma}, in human breast cancer cells.
C. Zang, H. Liu, J. Bertz, K. Possinger, H. P. Koeffler, E. Elstner, and J. Eucker (2009)
Mol. Cancer Ther.
8, 2296-2307
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Activation of the Akt-NF-{kappa}B Pathway by Subtilase Cytotoxin through the ATF6 Branch of the Unfolded Protein Response.
H. Yamazaki, N. Hiramatsu, K. Hayakawa, Y. Tagawa, M. Okamura, R. Ogata, T. Huang, S. Nakajima, J. Yao, A. W. Paton, et al. (2009)
J. Immunol.
183, 1480-1487
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The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease.
J. L. Portis, P. Askovich, J. Austin, Y. Gutierrez-Cotto, and F. J. McAtee (2009)
J. Virol.
83, 6079-6086
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Dehydrocostuslactone, a Medicinal Plant-Derived Sesquiterpene Lactone, Induces Apoptosis Coupled to Endoplasmic Reticulum Stress in Liver Cancer Cells.
Y.-L. Hsu, L.-Y. Wu, and P.-L. Kuo (2009)
J. Pharmacol. Exp. Ther.
329, 808-819
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(eIF2
Gly745 (L745G)] mutation rendered yeast IRE1 sensitive to 1NM-PP1. We therefore constructed an allele of human IRE1 in which the orthologous amino acid [isoleucine 642 (Ile642)] was changed to glycine [
25% reduction in viable cell number). 
