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

The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability tomeet protein-folding demand leads to ER stress, and activates IRE1 alpha, an ER transmembrane kinase-endoribonuclease (RNase). IRE1 alpha promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1 alpha 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 IRE1 alpha endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1 alpha regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.