Endoplasmic Reticulum (ER) Stress-induced Reactive Oxygen Species (ROS) Are Detrimental for the Fitness of a Thioredoxin Reductase Mutant

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2018 Jun 7

PMID 29871930

Citations 18

Authors

Paraskevi Kritsiligkou

Jonathan D Rand

Alan J Weids

Ximeng Wang

Chris J Kershaw

Chris M Grant

Affiliations

Soon will be listed here.

Abstract

The unfolded protein response (UPR) is constitutively active in yeast thioredoxin reductase mutants, suggesting a link between cytoplasmic thiol redox control and endoplasmic reticulum (ER) oxidative protein folding. The unique oxidative environment of the ER lumen requires tight regulatory control, and we show that the active UPR depends on the presence of oxidized thioredoxins rather than arising because of a loss of thioredoxin function. Preventing activation of the UPR by deletion of , encoding the UPR transcription factor, rescues a number of thioredoxin reductase mutant phenotypes, including slow growth, shortened longevity, and oxidation of the cytoplasmic GSH pool. This is because the constitutive UPR in a thioredoxin reductase mutant results in the generation of hydrogen peroxide. The oxidation of thioredoxins in a thioredoxin reductase mutant requires aerobic metabolism and the presence of the Tsa1 and Tsa2 peroxiredoxins, indicating that a complete cytoplasmic thioredoxin system is crucial for maintaining ER redox homeostasis.

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References

Sidrauski C, Cox J, Walter P . tRNA ligase is required for regulated mRNA splicing in the unfolded protein response. Cell. 1996; 87(3):405-13. DOI: 10.1016/s0092-8674(00)81361-6. View

Back S, Kaufman R . Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012; 81:767-93. PMC: 3684428. DOI: 10.1146/annurev-biochem-072909-095555. View

Okazaki S, Naganuma A, Kuge S . Peroxiredoxin-mediated redox regulation of the nuclear localization of Yap1, a transcription factor in budding yeast. Antioxid Redox Signal. 2005; 7(3-4):327-34. DOI: 10.1089/ars.2005.7.327. View

Gross E, Sevier C, Heldman N, Vitu E, Bentzur M, Kaiser C . Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Proc Natl Acad Sci U S A. 2006; 103(2):299-304. PMC: 1326156. DOI: 10.1073/pnas.0506448103. View

Williams C, Arscott L, Muller S, Lennon B, Ludwig M, Wang P . Thioredoxin reductase two modes of catalysis have evolved. Eur J Biochem. 2000; 267(20):6110-7. DOI: 10.1046/j.1432-1327.2000.01702.x. View

Cox J, Shamu C, Walter P . Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 1993; 73(6):1197-206. DOI: 10.1016/0092-8674(93)90648-a. View

Kimata Y, Ishiwata-Kimata Y, Yamada S, Kohno K . Yeast unfolded protein response pathway regulates expression of genes for anti-oxidative stress and for cell surface proteins. Genes Cells. 2005; 11(1):59-69. DOI: 10.1111/j.1365-2443.2005.00921.x. View

Pincus D, Chevalier M, Aragon T, van Anken E, Vidal S, El-Samad H . BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol. 2010; 8(7):e1000415. PMC: 2897766. DOI: 10.1371/journal.pbio.1000415. View

Trotter E, Grant C . Non-reciprocal regulation of the redox state of the glutathione-glutaredoxin and thioredoxin systems. EMBO Rep. 2003; 4(2):184-8. PMC: 1315827. DOI: 10.1038/sj.embor.embor729. View

10.

Stocker S, Van Laer K, Mijuskovic A, Dick T . The Conundrum of Hydrogen Peroxide Signaling and the Emerging Role of Peroxiredoxins as Redox Relay Hubs. Antioxid Redox Signal. 2017; 28(7):558-573. DOI: 10.1089/ars.2017.7162. View

11.

Pearson G, Merrill G . Deletion of the Saccharomyces cerevisiae TRR1 gene encoding thioredoxin reductase inhibits p53-dependent reporter gene expression. J Biol Chem. 1998; 273(10):5431-4. DOI: 10.1074/jbc.273.10.5431. View

12.

Delaunay A, Pflieger D, Barrault M, Vinh J, Toledano M . A thiol peroxidase is an H2O2 receptor and redox-transducer in gene activation. Cell. 2002; 111(4):471-81. DOI: 10.1016/s0092-8674(02)01048-6. View

13.

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

14.

Kojer K, Bien M, Gangel H, Morgan B, Dick T, Riemer J . Glutathione redox potential in the mitochondrial intermembrane space is linked to the cytosol and impacts the Mia40 redox state. EMBO J. 2012; 31(14):3169-82. PMC: 3400016. DOI: 10.1038/emboj.2012.165. View

15.

Machado A, Morgan B, Merrill G . Thioredoxin reductase-dependent inhibition of MCB cell cycle box activity in Saccharomyces cerevisiae. J Biol Chem. 1997; 272(27):17045-54. DOI: 10.1074/jbc.272.27.17045. View

16.

Deponte M, Lillig C . Enzymatic control of cysteinyl thiol switches in proteins. Biol Chem. 2015; 396(5):401-13. DOI: 10.1515/hsz-2014-0280. View

17.

Weids A, Grant C . The yeast peroxiredoxin Tsa1 protects against protein-aggregate-induced oxidative stress. J Cell Sci. 2014; 127(Pt 6):1327-35. PMC: 3953820. DOI: 10.1242/jcs.144022. View

18.

Rose M, Botstein D . Construction and use of gene fusions to lacZ (beta-galactosidase) that are expressed in yeast. Methods Enzymol. 1983; 101:167-80. DOI: 10.1016/0076-6879(83)01012-5. View

19.

Stearman R, Gasch A, Botstein D, Brown P, Storz G . Role of thioredoxin reductase in the Yap1p-dependent response to oxidative stress in Saccharomyces cerevisiae. Mol Microbiol. 2001; 39(3):595-605. DOI: 10.1046/j.1365-2958.2001.02255.x. View

20.

Draculic T, Dawes I, Grant C . A single glutaredoxin or thioredoxin gene is essential for viability in the yeast Saccharomyces cerevisiae. Mol Microbiol. 2000; 36(5):1167-74. DOI: 10.1046/j.1365-2958.2000.01948.x. View