XB-ART-40434Cell. August 7, 2009; 138 (3): 562-75.
IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates.
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) IRE1alpha is a key component of this apoptotic switch. ER stress induces IRE1alpha kinase autophosphorylation, activating the RNase to splice XBP1 mRNA and produce the homeostatic transcription factor XBP1s. Under ER stress--or forced autophosphorylation--IRE1alpha''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 IRE1alpha can be reconstituted in vitro. We propose that divergent cell fates during ER stress hinge on a balance between IRE1alpha RNase outputs that can be tilted with kinase inhibitors to favor survival.
PubMed ID: 19665977
PMC ID: PMC2762408
Article link: Cell.
Grant support: DP2 OD001925 NCCDPHP CDC HHS, K08 AI054650 NIAID NIH HHS , K08 DK065671 NIDDK NIH HHS , R01 DK080955 NIDDK NIH HHS , R01CA136577 NCI NIH HHS , R25 GM56847 NIGMS NIH HHS , Howard Hughes Medical Institute , DP2 OD001925-01 NCCDPHP CDC HHS, K08 DK065671-05 NIDDK NIH HHS , R01 DK080955-01A1 NIDDK NIH HHS , DP2 OD001925 NIH HHS , DP2 OD001925-01 NIH HHS , K08 DK065671-05 NIDDK NIH HHS , R01 CA136577 NCI NIH HHS , R01CA136577 NCI NIH HHS , R01 DK080955-01A1 NIDDK NIH HHS , K08 DK065671 NIDDK NIH HHS , DP2 OD001925-01 NIH HHS , Howard Hughes Medical Institute , K08 AI054650 NIAID NIH HHS , R01 DK080955 NIDDK NIH HHS , DP2 OD001925 NIH HHS , R25 GM56847 NIGMS NIH HHS , R25 GM056847 NIGMS NIH HHS
Genes referenced: xbp1