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

doi:10.1083/jcb.153.5.1011

Published online 28 May 2001. doi:10.1083/jcb.153.5.1011

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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

Original Article

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

Isabel Novoa^a, Huiqing Zeng^a, Heather P. Harding^a, and David Ron^a^,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
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 ${alpha}$ subunit of eukaryotic translation initiationfactor 2 (eIF2 ${alpha}$ ) on serine 51 integrates general translationrepression with activation of stress-inducible genes such asATF4, CHOP, and BiP in the unfolded protein response. We soughtto identify new genes active in this phospho-eIF2 ${alpha}$ –dependentsignaling pathway by screening a library of recombinant retrovirusesfor clones that inhibit the expression of a CHOP::GFP reporter.A retrovirus encoding the COOH terminus of growth arrest andDNA 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. NucleicAcid Res. 18:2823), was isolated and found to attenuate CHOP(also known as GADD153) activation by both protein malfoldingin the endoplasmic reticulum, and amino acid deprivation. Despitenormal activity of the cognate stress-inducible eIF2 ${alpha}$ kinasesPERK (also known as PEK) and GCN2, phospho-eIF2 ${alpha}$ levels weremarkedly diminished in GADD34-overexpressing cells. GADD34 formeda complex with the catalytic subunit of protein phosphatase1 (PP1c) that specifically promoted the dephosphorylation ofeIF2 ${alpha}$ in vitro. Mutations that interfered with the interactionwith PP1c prevented the dephosphorylation of eIF2 ${alpha}$ and blockedattenuation of CHOP by GADD34. Expression of GADD34 is stressdependent, and was absent in PERK^–/– and GCN2^–/–cells. These findings implicate GADD34-mediated dephosphorylationof eIF2 ${alpha}$ in a negative feedback loop that inhibits stress-inducedgene expression, and that might promote recovery from translationalinhibition in the unfolded protein response.

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

Abbreviations used in this paper: ATF, activating transcriptionfactor; BiP, immunoglobulin binding protein of B cells; CHOP,C/EBP homologous protein; eIF2 ${alpha}$ , eukaryotic translation initiationfactor 2 ${alpha}$ ; GADD, growth arrest and DNA damage gene; GAPDH, glutaraldehyde3-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-strandedRNA–activated-kinase; PP1, protein phosphatase 1; UPR,unfolded protein response.

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Cheng, G., Yang, K., He, B. (2003). Dephosphorylation of eIF-2{alpha} Mediated by the {gamma}134.5 Protein of Herpes Simplex Virus Type 1 Is Required for Viral Response to Interferon but Is Not Sufficient for Efficient Viral Replication. J. Virol. 77: 10154-10161 [Abstract] [Full Text]
Ma, Y., Hendershot, L. M. (2003). Delineation of a Negative Feedback Regulatory Loop That Controls Protein Translation during Endoplasmic Reticulum Stress. J. Biol. Chem. 278: 34864-34873 [Abstract] [Full Text]
Hung, W. J., Roberson, R. S., Taft, J., Wu, D. Y. (2003). Human BAG-1 Proteins Bind to the Cellular Stress Response Protein GADD34 and Interfere with GADD34 Functions. Mol. Cell. Biol. 23: 3477-3486 [Abstract] [Full Text]
van Huizen, R., Martindale, J. L., Gorospe, M., Holbrook, N. J. (2003). P58IPK, a Novel Endoplasmic Reticulum Stress-inducible Protein and Potential Negative Regulator of eIF2alpha Signaling. J. Biol. Chem. 278: 15558-15564 [Abstract] [Full Text]
Ward, S. L., Scheuner, D., Poppers, J., Kaufman, R. J., Mohr, I., Leib, D. A. (2003). In Vivo Replication of an ICP34.5 Second-Site Suppressor Mutant following Corneal Infection Correlates with In Vitro Regulation of eIF2{alpha} Phosphorylation. J. Virol. 77: 4626-4634 [Abstract] [Full Text]
Brush, M. H., Weiser, D. C., Shenolikar, S. (2003). Growth Arrest and DNA Damage-Inducible Protein GADD34 Targets Protein Phosphatase 1{alpha} to the Endoplasmic Reticulum and Promotes Dephosphorylation of the {alpha} Subunit of Eukaryotic Translation Initiation Factor 2. Mol. Cell. Biol. 23: 1292-1303 [Abstract] [Full Text]
Yan, W., Frank, C. L., Korth, M. J., Sopher, B. L., Novoa, I., Ron, D., Katze, M. G. (2002). Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc. Natl. Acad. Sci. USA 99: 15920-15925 [Abstract] [Full Text]
Harding, H. P., Ron, D. (2002). Endoplasmic Reticulum Stress and the Development of Diabetes: A Review. Diabetes 51: S455-461 [Abstract] [Full Text]
Terry-Lorenzo, R. T., Elliot, E., Weiser, D. C., Prickett, T. D., Brautigan, D. L., Shenolikar, S. (2002). Neurabins Recruit Protein Phosphatase-1 and Inhibitor-2 to the Actin Cytoskeleton. J. Biol. Chem. 277: 46535-46543 [Abstract] [Full Text]
Gill, A., Gao, N., Lehrman, M. A. (2002). Rapid Activation of Glycogen Phosphorylase by the Endoplasmic Reticulum Unfolded Protein Response. J. Biol. Chem. 277: 44747-44753 [Abstract] [Full Text]
Koumenis, C., Naczki, C., Koritzinsky, M., Rastani, S., Diehl, A., Sonenberg, N., Koromilas, A., Wouters, B. G. (2002). Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2{alpha}. Mol. Cell. Biol. 22: 7405-7416 [Abstract] [Full Text]
Cheng, G., Brett, M.-E., He, B. (2002). Signals That Dictate Nuclear, Nucleolar, and Cytoplasmic Shuttling of the {gamma}134.5 Protein of Herpes Simplex Virus Type 1. J. Virol. 76: 9434-9445 [Abstract] [Full Text]
Bushell, M., Sarnow, P. (2002). Hijacking the translation apparatus by RNA viruses. JCB 158: 395-399 [Abstract] [Full Text]
Abcouwer, S. F., Marjon, P. L., Loper, R. K., Vander Jagt, D. L. (2002). Response of VEGF Expression to Amino Acid Deprivation and Inducers of Endoplasmic Reticulum Stress. IOVS 43: 2791-2798 [Abstract] [Full Text]
Wu, D. Y., Tkachuck, D. C., Roberson, R. S., Schubach, W. H. (2002). The Human SNF5/INI1 Protein Facilitates the Function of the Growth Arrest and DNA Damage-inducible Protein (GADD34) and Modulates GADD34-bound Protein Phosphatase-1 Activity. J. Biol. Chem. 277: 27706-27715 [Abstract] [Full Text]