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© The Rockefeller University Press, 0021-9525/2001//1011 $5.00
The Journal of Cell Biology, Volume 153, Number 5, , 2001 1011-1022

Feedback Inhibition of the Unfolded Protein Response by GADD34-Mediated Dephosphorylation of eIF2

^a Skirball Institute of Biomolecular Medicine, Department of Medicine
^b Department of Cell Biology, Kaplan Cancer Center, New York University School of Medicine, New York, New York 10016
New York University Medical Center, SI 3-10, 540 First Ave., New York, NY 10016.(212) 263-8951(212) 263-7786

ron{at}saturn.med.nyu.edu

Phosphorylation of the subunit of eukaryotic translation initiation factor 2 (eIF2) on serine 51 integrates general translation repression with activation of stress-inducible genes such as ATF4, CHOP, and BiP in the unfolded protein response. We sought to identify new genes active in this phospho-eIF2–dependent signaling pathway by screening a library of recombinant retroviruses for clones that inhibit the expression of a CHOP::GFP reporter. A retrovirus encoding the COOH terminus of growth arrest and DNA damage gene (GADD)34, also known as MYD116 (Fornace, A.J., D.W. Neibert, M.C. Hollander, J.D. Luethy, M. Papathanasiou, J. Fragoli, and N.J. Holbrook. 1989. Mol. Cell. Biol. 9:4196–4203; Lord K.A., B. Hoffman-Lieberman, and D.A. Lieberman. 1990. Nucleic Acid Res. 18:2823), was isolated and found to attenuate CHOP (also known as GADD153) activation by both protein malfolding in the endoplasmic reticulum, and amino acid deprivation. Despite normal activity of the cognate stress-inducible eIF2 kinases PERK (also known as PEK) and GCN2, phospho-eIF2 levels were markedly diminished in GADD34-overexpressing cells. GADD34 formed a complex with the catalytic subunit of protein phosphatase 1 (PP1c) that specifically promoted the dephosphorylation of eIF2 in vitro. Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2 and blocked attenuation of CHOP by GADD34. Expression of GADD34 is stress dependent, and was absent in PERK^–/– and GCN2^–/– cells. These findings implicate GADD34-mediated dephosphorylation of eIF2 in a negative feedback loop that inhibits stress-induced gene expression, and that might promote recovery from translational inhibition in the unfolded protein response.

Key Words: endoplasmic reticulum • translation • gene expression regulation • signal transduction • molecular cloning

© 2001 The Rockefeller University Press

Abbreviations used in this paper: ATF, activating transcription factor; BiP, immunoglobulin binding protein of B cells; CHOP, C/EBP homologous protein; eIF2, eukaryotic translation initiation factor 2 ; GADD, growth arrest and DNA damage gene; GAPDH, glutaraldehyde 3-phosphate dehydrogenase; GCN, general control nonrepressed; GFP, green fluorescent protein; GSE, genetic suppressor element; GST, glutathione S-transferase; HSV, herpes simplex virus; MMS, methyl methanesulfonate; PERK, PKR-like ER kinase; PKR, double-stranded RNA–activated-kinase; PP1, protein phosphatase 1; UPR, unfolded protein response.

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