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Published 24 November 2003. doi:10.1083/jcb.200308075
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© The Rockefeller University Press, 0021-9525/2003/11/767 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 767-775

Article

Inhibition of a constitutive translation initiation factor 2{alpha} phosphatase, CReP, promotes survival of stressed cells



Céline Jousse1, Seiichi Oyadomari1, Isabel Novoa1, Phoebe Lu1, Yuhong Zhang1, Heather P. Harding2 and David Ron1

1 Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016
2 Department of Pharmacology, New York University School of Medicine, New York, NY 10016

Address correspondence to David Ron, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, SI 3-10, 540 First Ave., New York, NY 10016. Tel.: (212) 263-7786. Fax: (212) 263-8951. email: ron{at}saturn.med.nyu.edu

Phosphorylation of eukaryotic translation initiation factor 2{alpha} (eIF2{alpha}) on serine 51 is effected by specific stress-activated protein kinases. eIF2{alpha} phosphorylation inhibits translation initiation promoting a cytoprotective gene expression program known as the integrated stress response (ISR). Stress-induced activation of GADD34 feeds back negatively on this pathway by promoting eIF2{alpha} dephosphorylation, however, GADD34 mutant cells retain significant eIF2{alpha}-directed phosphatase activity. We used a somatic cell genetic approach to identify a gene encoding a novel regulatory subunit of a constitutively active holophosphatase complex that dephosphorylates eIF2{alpha}. RNAi of this gene, which we named constitutive repressor of eIF2{alpha} phosphorylation (CReP, or PPP1R15B), repressed the constitutive eIF2{alpha}-directed phosphatase activity and activated the ISR. CReP RNAi strongly protected mammalian cells against oxidative stress, peroxynitrite stress, and more modestly against accumulation of malfolded proteins in the endoplasmic reticulum. These findings suggest that therapeutic inhibition of eIF2{alpha} dephosphorylation by targeting the CReP-protein–phosphatase-1 complex may be used to access the salubrious qualities of the ISR.

Key Words: signal transduction; protein folding; pre-conditioning; somatic cell genetics; translation control

Abbreviations used in this paper: CReP, constitutive repressor of eIF2{alpha} phosphorylation; DCF, dichlorofluorescein; eIF2, eukaryotic translation initiation factor 2; ES, embryonic stem; ISR, integrated stress response; PI, propidium iodide; PP1c, protein phosphatase-1 catalytic subunit.


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