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Published online 21 May 2001. doi:10.1083/jcb.153.5.1011
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© The Rockefeller University Press, 0021-9525/2001/5/1011/ $5.00
The Journal of Cell Biology, Volume 153, Number 5, May 28, 2001 1011-1022

Original Article

Feedback Inhibition of the Unfolded Protein Response by GADD34-mediated Dephosphorylation of eIF2{alpha}

Isabel Novoaa, Huiqing Zenga, Heather P. Hardinga, and David Rona,b
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

Correspondence to: David Ron, New York University Medical Center, SI 3-10, 540 First Ave., New York, NY 10016. Tel:(212) 263-7786 Fax:(212) 263-8951 E-mail:ron{at}saturn.med.nyu.edu.

Phosphorylation of the {alpha} subunit of eukaryotic translation initiation factor 2 (eIF2{alpha}) 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{alpha}–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{alpha} kinases PERK (also known as PEK) and GCN2, phospho-eIF2{alpha} 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{alpha} in vitro. Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2{alpha} 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{alpha} 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


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