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

  1. Omer Kabil1*
  1. 1 University of Michigan Medical School, Ann Arbor, United States;
  2. 2 Case Western Reserve University, United States;
  3. 3 Lerner Research Institute, Cleveland Clinic, United States
  1. ↵* Corresponding author; email: omerk{at}umich.edu

  1. Author contributions: VY performed majority of the experiments and analyzed the data. X-HG contributed with his expertise in preparing samples for detection of PP1c persulfidation. BW performed the mass spectroscopy analysis with LC-MS/MS. MH contributed to designing of study related to ISR, data analysis and manuscript preparation. RB contributed to data analysis and helped in manuscript preparation. OK conceived and designed the study, analyzed and interpreted the data, performed experiments and prepared the manuscript. All authors approved the final version of the manuscript.

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 transsulfuration pathway. Here, we demonstrate that increased endogenous H2S production or its exogenous administration modulates major components of the integrated stress response (ISR) 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 (eIF2α-P) was mediated at least in part by inhibition of protein phosphatase-1 (PP1c) via persulfidation at Cys127. Overexpression of a PP1c cysteine mutant (C127S-PP1c) abrogated the H2S effect on eIF2α phosphorylation. Our data supports a model in which H2S exerts its cytoprotective effect on ISR signaling by inducing a transient adaptive reprogramming of global mRNA translation. While a transient increase in endogenous H2S production provides cytoprotection, its chronic increase such as in CBS deficiency may pose a problem.

  • Received January 26, 2017.
  • Accepted June 21, 2017.

This Article

  1. First Published on June 21, 2017 doi: 10.1074/jbc.M117.778654 jbc.M117.778654.
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