Feedback Inhibition of the Unfolded Protein Response by GADD34-mediated Dephosphorylation of EIF2alpha

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2001 May 31

PMID 11381086

Citations 686

Authors

I Novoa

H Zeng

H P Harding

D Ron

Affiliations

Soon will be listed here.

Abstract

Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) 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-eIF2alpha-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 eIF2alpha kinases PERK (also known as PEK) and GCN2, phospho-eIF2alpha 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 eIF2alpha in vitro. Mutations that interfered with the interaction with PP1c prevented the dephosphorylation of eIF2alpha 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 eIF2alpha in a negative feedback loop that inhibits stress-induced gene expression, and that might promote recovery from translational inhibition in the unfolded protein response.

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References

English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S . New insights into the control of MAP kinase pathways. Exp Cell Res. 1999; 253(1):255-70. DOI: 10.1006/excr.1999.4687. View

Berlanga J, Santoyo J, de Haro C . Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2alpha kinase. Eur J Biochem. 1999; 265(2):754-62. DOI: 10.1046/j.1432-1327.1999.00780.x. View

Sood R, Porter A, Ma K, Quilliam L, Wek R . Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. Biochem J. 2000; 346 Pt 2:281-93. PMC: 1220852. View

Sood R, Porter A, Olsen D, Cavener D, Wek R . A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Genetics. 2000; 154(2):787-801. PMC: 1460965. DOI: 10.1093/genetics/154.2.787. View

Mori K . Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 2000; 101(5):451-4. DOI: 10.1016/s0092-8674(00)80855-7. View

Bertolotti A, Zhang Y, Hendershot L, Harding H, Ron D . Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000; 2(6):326-32. DOI: 10.1038/35014014. View

Harding H, Zhang Y, Bertolotti A, Zeng H, Ron D . Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000; 5(5):897-904. DOI: 10.1016/s1097-2765(00)80330-5. View

Krebs D, Hilton D . SOCS: physiological suppressors of cytokine signaling. J Cell Sci. 2000; 113 ( Pt 16):2813-9. DOI: 10.1242/jcs.113.16.2813. View

Harding H, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M . Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000; 6(5):1099-108. DOI: 10.1016/s1097-2765(00)00108-8. View

10.

Scorsone K, Panniers R, Rowlands A, HENSHAW E . Phosphorylation of eukaryotic initiation factor 2 during physiological stresses which affect protein synthesis. J Biol Chem. 1987; 262(30):14538-43. View

11.

Williams N, Hinnebusch A, Donahue T . Mutations in the structural genes for eukaryotic initiation factors 2 alpha and 2 beta of Saccharomyces cerevisiae disrupt translational control of GCN4 mRNA. Proc Natl Acad Sci U S A. 1989; 86(19):7515-9. PMC: 298095. DOI: 10.1073/pnas.86.19.7515. View

12.

Fornace Jr A, Nebert D, Hollander M, Luethy J, Papathanasiou M, Fargnoli J . Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol. 1989; 9(10):4196-203. PMC: 362498. DOI: 10.1128/mcb.9.10.4196-4203.1989. View

13.

LORD K, Liebermann D . Sequence of MyD116 cDNA: a novel myeloid differentiation primary response gene induced by IL6. Nucleic Acids Res. 1990; 18(9):2823. PMC: 330781. DOI: 10.1093/nar/18.9.2823. View

14.

Morgenstern J, Land H . Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990; 18(12):3587-96. PMC: 331014. DOI: 10.1093/nar/18.12.3587. View

15.

Dever T, Feng L, Wek R, Cigan A, Donahue T, Hinnebusch A . Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell. 1992; 68(3):585-96. DOI: 10.1016/0092-8674(92)90193-g. View

16.

Landau N, Littman D . Packaging system for rapid production of murine leukemia virus vectors with variable tropism. J Virol. 1992; 66(8):5110-3. PMC: 241381. DOI: 10.1128/JVI.66.8.5110-5113.1992. View

17.

Prostko C, Brostrom M, Malara E, Brostrom C . Phosphorylation of eukaryotic initiation factor (eIF) 2 alpha and inhibition of eIF-2B in GH3 pituitary cells by perturbants of early protein processing that induce GRP78. J Biol Chem. 1992; 267(24):16751-4. View

18.

Wek R, CANNON J, Dever T, Hinnebusch A . Truncated protein phosphatase GLC7 restores translational activation of GCN4 expression in yeast mutants defective for the eIF-2 alpha kinase GCN2. Mol Cell Biol. 1992; 12(12):5700-10. PMC: 360510. DOI: 10.1128/mcb.12.12.5700-5710.1992. View

19.

Vallejo M, Ron D, Miller C, Habener J . C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements. Proc Natl Acad Sci U S A. 1993; 90(10):4679-83. PMC: 46576. DOI: 10.1073/pnas.90.10.4679. View

20.

Zhan Q, LORD K, Alamo Jr I, Hollander M, Carrier F, Ron D . The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth. Mol Cell Biol. 1994; 14(4):2361-71. PMC: 358603. DOI: 10.1128/mcb.14.4.2361-2371.1994. View