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

Publication Type:

Journal Article


Science, Volume 338, Issue 6108, p.818-22 (2012)


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


<p>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.</p>