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

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