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

+ See all authors and affiliations

Science  04 Oct 2012:
DOI: 10.1126/science.1226191

You are currently viewing the abstract.

View Full Text


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.

View Full Text