Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response
Jonathan H. Lin,1,2,3*Han Li,1,2Douglas Yasumura,4Hannah R. Cohen,2Chao Zhang,1,5Barbara Panning,2Kevan M. Shokat,1,5Matthew M. LaVail,4Peter Walter1,2
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 editors suggest the following Related Resources on Science sites:
In Science Signaling
EDITORS' CHOICE
Stella M. Hurtley (13 November 2007) Sci. STKE2007 (412), tw412.
[DOI: 10.1126/stke.4122007tw412] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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
|Abstract »|Full Text »|PDF »
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
|Abstract »|Full Text »|PDF »
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
|Abstract »|Full Text »|PDF »
Peroxisome Deficiency Causes a Complex Phenotype because of Hepatic SREBP/Insig Dysregulation Associated with Endoplasmic Reticulum Stress.
W. J. Kovacs, K. N. Tape, J. E. Shackelford, T. M. Wikander, M. J. Richards, S. J. Fliesler, S. K. Krisans, and P. L. Faust (2009)
J. Biol. Chem.
284, 7232-7245
|Abstract »|Full Text »|PDF »
ABCA4 disease progression and a proposed strategy for gene therapy.
A. V. Cideciyan, M. Swider, T. S. Aleman, Y. Tsybovsky, S. B. Schwartz, E. A.M. Windsor, A. J. Roman, A. Sumaroka, J. D. Steinberg, S. G. Jacobson, et al. (2009)
Hum. Mol. Genet.
18, 931-941
|Abstract »|Full Text »|PDF »
Expression pattern of XBP1(S) in human B-cell lymphomas.
L. Maestre, R. Tooze, M. Canamero, S. Montes-Moreno, R. Ramos, G. Doody, M. Boll, S. Barrans, S. Baena, M. A. Piris, et al. (2009)
Haematologica
94, 419-422
|Abstract »|Full Text »|PDF »
The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response.
G. Pagnan, D. Di Paolo, R. Carosio, F. Pastorino, D. Marimpietri, C. Brignole, A. Pezzolo, M. Loi, L. J.V. Galietta, F. Piccardi, et al. (2009)
Clin. Cancer Res.
15, 1199-1209
|Abstract »|Full Text »|PDF »
The Unfolded Protein Response and Autophagy: Herpesviruses Rule!.
D. Y. Lee, J. Lee, and B. Sugden (2009)
J. Virol.
83, 1168-1172
|Full Text »|PDF »
Basal Levels of eIF2{alpha} Phosphorylation Determine Cellular Antioxidant Status by Regulating ATF4 and xCT Expression.
Effect of an Inducer of BiP, a Molecular Chaperone, on Endoplasmic Reticulum (ER) Stress-Induced Retinal Cell Death.
Y. Inokuchi, Y. Nakajima, M. Shimazawa, T. Kurita, M. Kubo, A. Saito, H. Sajiki, T. Kudo, M. Aihara, K. Imaizumi, et al. (2009)
Invest. Ophthalmol. Vis. Sci.
50, 334-344
|Abstract »|Full Text »|PDF »
Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death.
J. L. Little, F. B. Wheeler, C. Koumenis, and S. J. Kridel (2008)
Mol. Cancer Ther.
7, 3816-3824
|Abstract »|Full Text »|PDF »
Endoplasmic Reticulum Stress Markers Are Associated with Obesity in Nondiabetic Subjects.
N. K. Sharma, S. K. Das, A. K. Mondal, O. G. Hackney, W. S. Chu, P. A. Kern, N. Rasouli, H. J. Spencer, A. Yao-Borengasser, and S. C. Elbein (2008)
J. Clin. Endocrinol. Metab.
93, 4532-4541
|Abstract »|Full Text »|PDF »
Endoplasmic Reticulum Stress Regulator XBP-1 Contributes to Effector CD8+ T Cell Differentiation during Acute Infection.
Differential Control of the CCAAT/Enhancer-binding Protein {beta} (C/EBP{beta}) Products Liver-enriched Transcriptional Activating Protein (LAP) and Liver-enriched Transcriptional Inhibitory Protein (LIP) and the Regulation of Gene Expression during the Response to Endoplasmic Reticulum Stress.
Y. Li, E. Bevilacqua, C.-B. Chiribau, M. Majumder, C. Wang, C. M. Croniger, M. D. Snider, P. F. Johnson, and M. Hatzoglou (2008)
J. Biol. Chem.
283, 22443-22456
|Abstract »|Full Text »|PDF »
Effect of pioglitazone treatment on endoplasmic reticulum stress response in human adipose and in palmitate-induced stress in human liver and adipose cell lines.
S. K. Das, W. S. Chu, A. K. Mondal, N. K. Sharma, P. A. Kern, N. Rasouli, and S. C. Elbein (2008)
Am J Physiol Endocrinol Metab
295, E393-E400
|Abstract »|Full Text »|PDF »
Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces.
Initiation and execution of lipotoxic ER stress in pancreatic {beta}-cells.
D. A. Cunha, P. Hekerman, L. Ladriere, A. Bazarra-Castro, F. Ortis, M. C. Wakeham, F. Moore, J. Rasschaert, A. K. Cardozo, E. Bellomo, et al. (2008)
J. Cell Sci.
121, 2308-2318
|Abstract »|Full Text »|PDF »
Dolichol Biosynthesis and Its Effects on the Unfolded Protein Response and Abiotic Stress Resistance in Arabidopsis.
H. Zhang, K. Ohyama, J. Boudet, Z. Chen, J. Yang, M. Zhang, T. Muranaka, C. Maurel, J.-K. Zhu, and Z. Gong (2008)
PLANT CELL
20, 1879-1898
|Abstract »|Full Text »|PDF »
Coronavirus Infection Modulates the Unfolded Protein Response and Mediates Sustained Translational Repression.
J. Bechill, Z. Chen, J. W. Brewer, and S. C. Baker (2008)
J. Virol.
82, 4492-4501
|Abstract »|Full Text »|PDF »
The Unfolded Protein Response: A Pathway That Links Insulin Demand with {beta}-Cell Failure and Diabetes.
