IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2

Science. 2012 Nov 9;338(6108):818-22. doi: 10.1126/science.1226191. Epub 2012 Oct 4.

Abstract

The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein-folding demand leads to "ER stress," and activates IRE1α, an ER transmembrane kinase-endoribonuclease (RNase). IRE1α promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1α RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, and -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1α endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1α regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Apoptosis
  • Brefeldin A / pharmacology
  • Caspase 2 / genetics*
  • Caspase 2 / metabolism*
  • Cell-Free System
  • Cells, Cultured
  • Cysteine Endopeptidases / genetics*
  • Cysteine Endopeptidases / metabolism*
  • Down-Regulation
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress*
  • Endoribonucleases / chemistry
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Mutant Proteins
  • Protein Biosynthesis
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Up-Regulation

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Mutant Proteins
  • RNA, Messenger
  • Brefeldin A
  • ERN1 protein, human
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • CASP2 protein, human
  • Casp2 protein, mouse
  • Caspase 2
  • Cysteine Endopeptidases