PMID:20798350

Citation	Li, H, Korennykh, AV, Behrman, SL and Walter, P (2010) Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc. Natl. Acad. Sci. U.S.A. 107:16113-8
Abstract	Accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), an intracellular signaling pathway that adjusts the protein folding capacity of the ER according to need. If homeostasis in the ER protein folding environment cannot be reestablished, cells commit to apoptosis. The ER-resident transmembrane kinase-endoribonuclease inositol-requiring enzyme 1 (IRE1) is the best characterized UPR signal transduction molecule. In yeast, Ire1 oligomerizes upon activation in response to an accumulation of misfolded proteins in the ER. Here we show that the salient mechanistic features of IRE1 activation are conserved: mammalian IRE1 oligomerizes in the ER membrane and oligomerization correlates with the onset of IRE1 phosphorylation and RNase activity. Moreover, the kinase/RNase module of human IRE1 activates cooperatively in vitro, indicating that formation of oligomers larger than four IRE1 molecules takes place upon activation. High-order IRE1 oligomerization thus emerges as a conserved mechanism of IRE1 signaling. IRE1 signaling attenuates after prolonged ER stress. IRE1 then enters a refractive state even if ER stress remains unmitigated. Attenuation includes dissolution of IRE1 clusters, IRE1 dephosphorylation, and decline in endoribonuclease activity. Thus IRE1 activity is governed by a timer that may be important in switching the UPR from the initially cytoprotective phase to the apoptotic mode.
Links	PubMed PMC2941319 Online version:10.1073/pnas.1010580107
Keywords	Animals; Cells, Cultured; Endoplasmic Reticulum/metabolism; Endoribonucleases/chemistry; Endoribonucleases/metabolism; Homeostasis; Humans; Membrane Proteins/chemistry; Membrane Proteins/deficiency; Membrane Proteins/metabolism; Mice; Mice, Knockout; Models, Molecular; Phosphorylation; Protein Multimerization; Protein Structure, Quaternary; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/chemistry; Protein-Serine-Threonine Kinases/deficiency; Protein-Serine-Threonine Kinases/metabolism; Signal Transduction; Stress, Physiological
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ERN1	enables	GO:0042802: identical protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:O75460-1	F		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.