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Sci. Signal., 13 November 2012
Vol. 5, Issue 250, p. ec294
[DOI: 10.1126/scisignal.2003767]


Stress Signaling To Die For

Stella M. Hurtley

Science, AAAS, Cambridge CB2 1LQ, UK

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. now report that IRE1α is the ER stress sensor that activates caspase-2 and does so through a mechanism involving noncoding RNAs. Under irremediable ER stress, the RNase activity of IRE1α triggers the rapid decay of select microRNAs that normally repress translation of caspase-2 mRNA, rapidly increasing caspase-2 abundance as the first step in its activation.

J.-P. Upton, L. Wang, D. Han, E. S. Wang, N. E. Huskey, L. Lim, M. Truitt, M. T. McManus, D. Ruggero, A. Goga, F. R. Papa, S. A. Oakes, IRE1α cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science 338, 818–822 (2012). [Abstract] [Full Text]

Citation: S. M. Hurtley, To Die For. Sci. Signal. 5, ec294 (2012).

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