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

doi:10.1083/jcb.200308075

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 factor2 ${alpha}$ (eIF2 ${alpha}$ ) on serine 51 is effected by specific stress-activatedprotein kinases. eIF2 ${alpha}$ phosphorylation inhibits translation initiationpromoting a cytoprotective gene expression program known asthe integrated stress response (ISR). Stress-induced activationof GADD34 feeds back negatively on this pathway by promotingeIF2 ${alpha}$ dephosphorylation, however, GADD34 mutant cells retainsignificant eIF2 ${alpha}$ -directed phosphatase activity. We used a somaticcell genetic approach to identify a gene encoding a novel regulatorysubunit of a constitutively active holophosphatase complex thatdephosphorylates eIF2 ${alpha}$ . RNAi of this gene, which we named constitutiverepressor of eIF2 ${alpha}$ phosphorylation (CReP, or PPP1R15B), repressedthe constitutive eIF2 ${alpha}$ -directed phosphatase activity and activatedthe ISR. CReP RNAi strongly protected mammalian cells againstoxidative stress, peroxynitrite stress, and more modestly againstaccumulation of malfolded proteins in the endoplasmic reticulum.These findings suggest that therapeutic inhibition of eIF2 ${alpha}$ dephosphorylationby targeting the CReP-protein–phosphatase-1 complex maybe 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 repressorof eIF2 ${alpha}$ phosphorylation; DCF, dichlorofluorescein; eIF2, eukaryotictranslation initiation factor 2; ES, embryonic stem; ISR, integratedstress response; PI, propidium iodide; PP1c, protein phosphatase-1catalytic subunit.

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