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 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.
Lin
Jonathan H
JH
Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA. Jonathan.Lin@ucsf.edu
Li
Han
H
Yasumura
Douglas
D
Cohen
Hannah R
HR
Zhang
Chao
C
Panning
Barbara
B
Shokat
Kevan M
KM
Lavail
Matthew M
MM
Walter
Peter
P
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D012160:Retina / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism
D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D012243:Rhodopsin; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C403982:ERN2 protein, human