IRE1[alpha] Cleaves Select microRNAs During ER Stress to Derepress Translation of Proapoptotic Caspase-2

• Published in: Science (American Association for the Advancement of Science) 2012-11, Vol.338 (6108), p.818
• Main Authors: John-Paul, Upton, Wang, Likun, Han, Dan, Wang, Eric S, Huskey, Noelle E, Lim, Lionel, Truitt, Morgan, McManus, Michael T, Ruggero, Davide, Goga, Andrei, Papa, Feroz R, Oakes, Scott A
• Format: Article
• Language: English
• Subjects: Apoptosis; Cellular biology; Coding; Protein folding; RNA-protein interactions; Stress response; Translation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1226191

The unfolded protein response (UPR) adjusts the protein folding capacity of the endoplasmic reticulum (ER) to match demand. UPR signaling requires IRE1α, an ER transmembrane kinase-endoribonuclease (RNase) that becomes activated by unfolded protein accumulation within the ER and excises a segment in XBP1 messenger RNA (mRNA) to initiate production of the homeostatic transcription factor XBP1s. However, if ER stress is irremediable, sustained IRE1α RNase activity triggers cell death. Severe ER stress activates the protease Caspase-2 as an early apoptotic switch upstream of mitochondria. However, the molecular events leading from the detection of ER stress to Caspase-2 activation are unclear. Upton et al. (p. 818, published online 4 October) now report that IRE1α is the ER stress sensor that activates Caspase-2, and does so through a mechanism involving non-coding RNAs. Under irremediable ER stress, IRE1α's RNase triggers the rapid decay of select microRNAs that normally repress translation of Caspase-2 mRNA, rapidly increasing Caspase-2 levels as the first step in its activation. [PUBLICATION 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. [PUBLICATION ABSTRACT]