Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering

Han Li, Alexei V. Korennykh, Shannon L. Behrman, Peter Walter

Research output: Contribution to journalArticle

195 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16113-16118
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number37
DOIs
StatePublished - Sep 14 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Fluorescent microscopy
  • Kinase
  • Oligomerization
  • RNase
  • Receptor

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