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Science 338 (6108): 818-822

Copyright © 2012 by the American Association for the Advancement of Science

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

John-Paul Upton,1,7,* Likun Wang,2,6,8,* Dan Han,2,6,8 Eric S. Wang,1 Noelle E. Huskey,2,7 Lionel Lim,2,7 Morgan Truitt,3,7 Michael T. McManus,4,5,6 Davide Ruggero,3,8 Andrei Goga,2,8 Feroz R. Papa,2,5,7,9,{dagger} Scott A. Oakes1,8,{dagger}

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.

1 Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
2 Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
3 Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
4 Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
5 Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
6 Keck Center for Noncoding RNAs, University of California, San Francisco, San Francisco, CA 94143, USA.
7 Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA.
8 Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
9 California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: frpapa{at}medicine.ucsf.edu (F.R.P.) and scott.oakes{at}ucsf.edu (S.A.O.)


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