Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Cell
2009 Aug 07;1383:562-75. doi: 10.1016/j.cell.2009.07.017.
Show Gene links
Show Anatomy links
IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates.
Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR.
???displayArticle.abstract???
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.
Aragón,
Messenger RNA targeting to endoplasmic reticulum stress signalling sites.
2009,
Pubmed Boudeau,
Emerging roles of pseudokinases.
2006,
Pubmed Calfon,
IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA.
2002,
Pubmed Credle,
On the mechanism of sensing unfolded protein in the endoplasmic reticulum.
2005,
Pubmed Han,
A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress.
2008,
Pubmed Harding,
Translational regulation in the cellular response to biosynthetic load on the endoplasmic reticulum.
2001,
Pubmed Higashio,
A genetic link between the unfolded protein response and vesicle formation from the endoplasmic reticulum.
2002,
Pubmed Hollien,
Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response.
2006,
Pubmed Hollien,
Regulated Ire1-dependent decay of messenger RNAs in mammalian cells.
2009,
Pubmed Kaufman,
Orchestrating the unfolded protein response in health and disease.
2002,
Pubmed Korennykh,
The unfolded protein response signals through high-order assembly of Ire1.
2009,
Pubmed Lee,
XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response.
2003,
Pubmed Lee,
Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing.
2008,
Pubmed Lin,
Divergent effects of PERK and IRE1 signaling on cell viability.
2009,
Pubmed Lin,
IRE1 signaling affects cell fate during the unfolded protein response.
2007,
Pubmed Lipson,
The role of IRE1alpha in the degradation of insulin mRNA in pancreatic beta-cells.
2008,
Pubmed Louvet,
Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice.
2008,
Pubmed Merksamer,
Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions.
2008,
Pubmed Oyadomari,
Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes.
2002,
Pubmed Papa,
Bypassing a kinase activity with an ATP-competitive drug.
2003,
Pubmed Ron,
Signal integration in the endoplasmic reticulum unfolded protein response.
2007,
Pubmed Shah,
Engineering unnatural nucleotide specificity for Rous sarcoma virus tyrosine kinase to uniquely label its direct substrates.
1997,
Pubmed Shamu,
Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
1996,
Pubmed Støy,
Insulin gene mutations as a cause of permanent neonatal diabetes.
2007,
Pubmed Thomas,
Pattern of genes influenced by conditional expression of the transcription factors HNF6, HNF4alpha and HNF1beta in a pancreatic beta-cell line.
2004,
Pubmed Tirasophon,
A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells.
1998,
Pubmed Travers,
Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation.
2000,
Pubmed Urano,
Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1.
2000,
Pubmed Wang,
Cloning of mammalian Ire1 reveals diversity in the ER stress responses.
1998,
Pubmed Wei,
Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.
2001,
Pubmed Yoshida,
XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor.
2001,
Pubmed Zhou,
The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response.
2006,
Pubmed
