Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway

被引:26
|
作者
Yadav, Vinita [1 ]
Gao, Xing-Huang [2 ]
Willard, Belinda [3 ]
Hatzoglou, Maria [2 ]
Banerjee, Ruma [1 ]
Kabil, Omer [1 ]
机构
[1] Univ Michigan, Med Sch, Dept Biol Chem, Ann Arbor, MI 48109 USA
[2] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA
[3] Cleveland Clin, Lerner Res Inst, Prote & Metabol Lab, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; ISCHEMIA-REPERFUSION INJURY; CYSTATHIONINE BETA-SYNTHASE; TO-MESENCHYMAL TRANSITION; UNFOLDED PROTEIN RESPONSE; INDUCED HEART-FAILURE; CARDIAC DYSFUNCTION; IN-VITRO; H2S; CELLS;
D O I
10.1074/jbc.M117.778654
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (eIF2 alpha) resulting in inhibition of general protein synthesis. The H2S-induced increase in eIF2 alpha 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 eIF2 alpha 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 beta-synthase deficiency may pose a problem.
引用
收藏
页码:13143 / 13153
页数:11
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