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IRE1α Cleaves Select microRNAs during ER Stress to Derepress Translation of Proapoptotic Caspase-2

Science  04 Oct 2012:

DOI: 10.1126/science.1226191

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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, -125b) that normally repress translation of Caspase-2 mRNA, thus sharply elevating protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1α endonucleolytically cleaved miR precursors at sites distinct from DICER. Thus, IRE1α regulates translation of a proapoptotic protein through terminating miR biogenesis, and noncoding RNAs are part of the ER stress response.

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