IRE1 signaling affects cell fate during the unfolded protein response

Endoplasmic reticulum (ER) stress activates a set of signaling pathways, collectively termed the unfolded protein response (UPR). The three UPR branches (IRE1, PERK, and ATF6) promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) Vol. 318; no. 5852; p. 944
Main Authors: Lin, Jonathan H, Li, Han, Yasumura, Douglas, Cohen, Hannah R, Zhang, Chao, Panning, Barbara, Shokat, Kevan M, Lavail, Matthew M, Walter, Peter
Format: Journal Article
Language:English
Published: United States 09.11.2007
Subjects:
Activating Transcription Factor 6 - metabolism
Animals
Animals, Genetically Modified
Apoptosis
Cell Line
Cell Survival
Disease Models, Animal
eIF-2 Kinase - metabolism
Endoplasmic Reticulum - metabolism
Endoribonucleases - genetics
Endoribonucleases - metabolism
Humans
Kinetics
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mutation
Protein Folding
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Proteins - chemistry
Proteins - metabolism
Rats
Retina - metabolism
Retinitis Pigmentosa - metabolism
Rhodopsin - chemistry
Rhodopsin - metabolism
Signal Transduction
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary:Endoplasmic reticulum (ER) stress activates a set of signaling pathways, collectively termed the unfolded protein response (UPR). The three UPR branches (IRE1, PERK, and ATF6) promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. How the UPR integrates its cytoprotective and proapoptotic outputs to select between life or death cell fates is unknown. We found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and proapoptotic transcription regulator Chop induction, was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.1146361