Journal
CELL
Volume 138, Issue 3, Pages 562-575Publisher
CELL PRESS
DOI: 10.1016/j.cell.2009.07.017
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Funding
- National Institutes of Health [DP2 OD001925, K08 DK065671, RO1 DK080955, K08 A1054650, RO1 CA136577]
- NIGMS-IMSD [R25 GM56847]
- Howard Hughes Medical Institute Physician-Scientist Early Career Award
- Steward Trust Foundation
- Sandler Program in Basic Sciences
- Burroughs Wellcome Foundation
- Hillblom Foundation
- Partnership for Cures
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During endoplasmic reticulum ( ER) stress, homeostatic signaling through the unfolded protein response (UPR) augments ER protein-folding capacity. If homeostasis is not restored, the UPR triggers apoptosis. We found that the ER transmembrane kinase/endoribonuclease (RNase) IRE1 alpha is a key component of this apoptotic switch. ER stress induces IRE1 alpha kinase autophosphorylation, activating the RNase to splice XBP1 mRNA and produce the homeostatic transcription factor XBP1s. Under ER stress-or forced autophosphorylation-IRE1 alpha's RNase also causes endonucleolytic decay of many ER-localized mRNAs, including those encoding chaperones, as early events culminating in apoptosis. Using chemical genetics, we show that kinase inhibitors bypass autophosphorylation to activate the RNase by an alternate mode that enforces XBP1 splicing and averts mRNA decay and apoptosis. Alternate RNase activation by kinase-inhibited IRE1 alpha can be reconstituted in vitro. We propose that divergent cell fates during ER stress hinge on a balance between IRE1 alpha RNase outputs that can be tilted with kinase inhibitors to favor survival.
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