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Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway.
J Biol Chem. 2017 08 11; 292(32):13143-13153.JB

Abstract

Hydrogen sulfide (H2S) regulates various physiological processes, including neuronal activity, vascular tone, inflammation, and energy metabolism. Moreover, H2S elicits cytoprotective effects against stressors in various cellular models of injury. However, the mechanism of the signaling pathways mediating the cytoprotective functions of H2S is not well understood. We previously uncovered a heme-dependent metabolic switch for transient induction of H2S production in the trans-sulfuration pathway. Here, we demonstrate that increased endogenous H2S production or its exogenous administration modulates major components of the integrated stress response promoting a metabolic state primed for stress response. We show that H2S transiently increases phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) resulting in inhibition of general protein synthesis. The H2S-induced increase in eIF2α phosphorylation was mediated at least in part by inhibition of protein phosphatase-1 (PP1c) via persulfidation at Cys-127. Overexpression of a PP1c cysteine mutant (C127S-PP1c) abrogated the H2S effect on eIF2α phosphorylation. Our data support a model in which H2S exerts its cytoprotective effect on ISR signaling by inducing a transient adaptive reprogramming of global mRNA translation. Although a transient increase in endogenous H2S production provides cytoprotection, its chronic increase such as in cystathionine β-synthase deficiency may pose a problem.

Authors+Show Affiliations

From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109.the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, and.the Proteomics and Metabolomics Laboratory, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44106.the Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, and.From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109.From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, omerk@umich.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28637872

Citation

Yadav, Vinita, et al. "Hydrogen Sulfide Modulates Eukaryotic Translation Initiation Factor 2α (eIF2α) Phosphorylation Status in the Integrated Stress-response Pathway." The Journal of Biological Chemistry, vol. 292, no. 32, 2017, pp. 13143-13153.
Yadav V, Gao XH, Willard B, et al. Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway. J Biol Chem. 2017;292(32):13143-13153.
Yadav, V., Gao, X. H., Willard, B., Hatzoglou, M., Banerjee, R., & Kabil, O. (2017). Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway. The Journal of Biological Chemistry, 292(32), 13143-13153. https://doi.org/10.1074/jbc.M117.778654
Yadav V, et al. Hydrogen Sulfide Modulates Eukaryotic Translation Initiation Factor 2α (eIF2α) Phosphorylation Status in the Integrated Stress-response Pathway. J Biol Chem. 2017 08 11;292(32):13143-13153. PubMed PMID: 28637872.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway. AU - Yadav,Vinita, AU - Gao,Xing-Huang, AU - Willard,Belinda, AU - Hatzoglou,Maria, AU - Banerjee,Ruma, AU - Kabil,Omer, Y1 - 2017/06/21/ PY - 2017/01/26/received PY - 2017/06/21/revised PY - 2017/6/24/pubmed PY - 2017/8/26/medline PY - 2017/6/23/entrez KW - cytoprotection KW - eukaryotic initiation factor 2 (eIF2) KW - hydrogen sulfide KW - integrated stress response KW - phosphoprotein phosphatase 1 (PP1) KW - protein persulfidation KW - signaling KW - stress response KW - sulfhydration SP - 13143 EP - 13153 JF - The Journal of biological chemistry JO - J Biol Chem VL - 292 IS - 32 N2 - Hydrogen sulfide (H2S) regulates various physiological processes, including neuronal activity, vascular tone, inflammation, and energy metabolism. Moreover, H2S elicits cytoprotective effects against stressors in various cellular models of injury. However, the mechanism of the signaling pathways mediating the cytoprotective functions of H2S is not well understood. We previously uncovered a heme-dependent metabolic switch for transient induction of H2S production in the trans-sulfuration pathway. Here, we demonstrate that increased endogenous H2S production or its exogenous administration modulates major components of the integrated stress response promoting a metabolic state primed for stress response. We show that H2S transiently increases phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) resulting in inhibition of general protein synthesis. The H2S-induced increase in eIF2α phosphorylation was mediated at least in part by inhibition of protein phosphatase-1 (PP1c) via persulfidation at Cys-127. Overexpression of a PP1c cysteine mutant (C127S-PP1c) abrogated the H2S effect on eIF2α phosphorylation. Our data support a model in which H2S exerts its cytoprotective effect on ISR signaling by inducing a transient adaptive reprogramming of global mRNA translation. Although a transient increase in endogenous H2S production provides cytoprotection, its chronic increase such as in cystathionine β-synthase deficiency may pose a problem. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/28637872/Hydrogen_sulfide_modulates_eukaryotic_translation_initiation_factor_2α__eIF2α__phosphorylation_status_in_the_integrated_stress_response_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)38544-6 DB - PRIME DP - Unbound Medicine ER -