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

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

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1
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.

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.

PMID:
23042294
PMCID:
PMC3742121
DOI:
10.1126/science.1226191
[Indexed for MEDLINE]
Free PMC Article

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