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

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