CHOP Induces Death by Promoting Protein Synthesis and Oxidation in the Stressed Endoplasmic Reticulum

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2004 Dec 17

PMID 15601821

Citations 1016

Authors

Stefan J Marciniak

Chi Y Yun

Seiichi Oyadomari

Isabel Novoa

YuHong Zhang

Rivka Jungreis

Kazuhiro Nagata

Heather P Harding

David Ron

Affiliations

Soon will be listed here.

Abstract

Unfolded and malfolded client proteins impose a stress on the endoplasmic reticulum (ER), which contributes to cell death in pathophysiological conditions. The transcription factor C/EBP homologous protein (CHOP) is activated by ER stress, and CHOP deletion protects against its lethal consequences. We find that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells. Thus, impaired GADD34 expression reduces client protein load and ER stress in CHOP(-/-) cells exposed to perturbations that impair ER function. CHOP(-/-) and GADD34 mutant cells accumulate less high molecular weight protein complexes in their stressed ER than wild-type cells. Furthermore, mice lacking GADD34-directed eIF2alpha dephosphorylation, like CHOP(-/-) mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1alpha, which encodes an ER oxidase. Consequently, the ER of stressed CHOP(-/-) cells is relatively hypo-oxidizing. Pharmacological and genetic manipulations that promote a hypo-oxidizing ER reduce abnormal high molecular weight protein complexes in the stressed ER and protect from the lethal consequences of ER stress. CHOP deletion thus protects cells from ER stress by decreasing ER client protein load and changing redox conditions within the organelle.

Citing Articles

Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.

Peng C, Wang J, Wang S, Zhao Y, Wang H, Wang Y Cancer Med. 2025; 14(5):e70684.

PMID: 40035165 PMC: 11877002. DOI: 10.1002/cam4.70684.

Subcellular localization of SARS-CoV-2 E and 3a proteins along the secretory pathway.

Hinkle J, Trychta K, Wires E, Osborn R, Leach J, Faraz Z J Mol Histol. 2025; 56(2):98.

PMID: 40025386 PMC: 11872775. DOI: 10.1007/s10735-025-10375-w.

PERK-Olating Through Cancer: A Brew of Cellular Decisions.

Mazzolini L, Touriol C Biomolecules. 2025; 15(2).

PMID: 40001551 PMC: 11852789. DOI: 10.3390/biom15020248.

Common molecular profile of multiple structurally distinct warfare arsenicals in causing cutaneous chemical vesicant injury.

Srivastava R, Muzaffar S, Khan J, Bansal M, Agarwal A, Athar M Sci Rep. 2025; 15(1):6505.

PMID: 39987158 PMC: 11846883. DOI: 10.1038/s41598-024-83513-1.

PARP-16 regulates the PERK and IRE-1α Mediated Unfolded Protein Response in Japanese Encephalitis Virus-Infected Neural Stem/Progenitor Cells.

Sharma S, Satheesan A, Majumdar A, Mukherjee S, Basu A Mol Neurobiol. 2025; .

PMID: 39979689 DOI: 10.1007/s12035-025-04748-1.

References

Connor J, Weiser D, Li S, Hallenbeck J, Shenolikar S . Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1. Mol Cell Biol. 2001; 21(20):6841-50. PMC: 99861. DOI: 10.1128/MCB.21.20.6841-6850.2001. View

Kaufman R . Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002; 110(10):1389-98. PMC: 151822. DOI: 10.1172/JCI16886. View

Mezghrani A, Fassio A, Benham A, Simmen T, Braakman I, Sitia R . Manipulation of oxidative protein folding and PDI redox state in mammalian cells. EMBO J. 2001; 20(22):6288-96. PMC: 125306. DOI: 10.1093/emboj/20.22.6288. View

Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K . XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2002; 107(7):881-91. DOI: 10.1016/s0092-8674(01)00611-0. View

Shen X, Ellis R, Lee K, Liu C, Yang K, Solomon A . Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell. 2002; 107(7):893-903. DOI: 10.1016/s0092-8674(01)00612-2. 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

Meunier L, Usherwood Y, Chung K, Hendershot L . A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell. 2002; 13(12):4456-69. PMC: 138646. DOI: 10.1091/mbc.e02-05-0311. View

Jansens A, van Duijn E, Braakman I . Coordinated nonvectorial folding in a newly synthesized multidomain protein. Science. 2002; 298(5602):2401-3. DOI: 10.1126/science.1078376. View

Brush M, Weiser D, Shenolikar S . 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. 2003; 23(4):1292-303. PMC: 141149. DOI: 10.1128/MCB.23.4.1292-1303.2003. View

10.

Novoa I, Zhang Y, Zeng H, Jungreis R, Harding H, Ron D . Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 2003; 22(5):1180-7. PMC: 150345. DOI: 10.1093/emboj/cdg112. View

11.

Harding H, Zhang Y, Zeng H, Novoa I, Lu P, Calfon M . An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003; 11(3):619-33. DOI: 10.1016/s1097-2765(03)00105-9. View

12.

Feng B, Yao P, Li Y, Devlin C, Zhang D, Harding H . The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 2003; 5(9):781-92. DOI: 10.1038/ncb1035. View

13.

Ma Y, Hendershot L . Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem. 2003; 278(37):34864-73. DOI: 10.1074/jbc.M301107200. View

14.

Frand A, Kaiser C . Ero1p oxidizes protein disulfide isomerase in a pathway for disulfide bond formation in the endoplasmic reticulum. Mol Cell. 1999; 4(4):469-77. DOI: 10.1016/s1097-2765(00)80198-7. View

15.

Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner B . Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000; 403(6765):98-103. DOI: 10.1038/47513. View

16.

Frand A, Cuozzo J, Kaiser C . Pathways for protein disulphide bond formation. Trends Cell Biol. 2000; 10(5):203-10. DOI: 10.1016/s0962-8924(00)01745-1. View

17.

Travers K, Patil C, Wodicka L, Lockhart D, Weissman J, Walter P . Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell. 2000; 101(3):249-58. DOI: 10.1016/s0092-8674(00)80835-1. View

18.

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

19.

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

20.

Pagani M, Fabbri M, Benedetti C, Fassio A, Pilati S, Bulleid N . Endoplasmic reticulum oxidoreductin 1-lbeta (ERO1-Lbeta), a human gene induced in the course of the unfolded protein response. J Biol Chem. 2000; 275(31):23685-92. DOI: 10.1074/jbc.M003061200. View