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.
Highlights
Hydrogen sulfide (H2S) regulates various physiological processes, including neuronal activity, vascular tone, inflammation, and energy metabolism
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 have characterized an H2S signaling pathway using a cellular model system where endogenous H2S production was induced by overexpressing heme oxygenase-2 (HO-2)
Summary
Hydrogen sulfide (H2S) regulates various physiological processes, including neuronal activity, vascular tone, inflammation, and energy metabolism. H2S treatment increases resistance to ER stress in neuronal cells [34, 35], cardiomyocytes [36], and endothelial cells [37] It suppresses ER-induced endothelial to mesenchymal transdifferentiation [37], a pathological factor for progression of cardiac fibrosis [38], and reprograms cellular energy production in pancreatic beta cells in response to chronic ER stress [39]. ATF4 activates expression of stress-response genes and promotes proteostasis via a feedback loop that involves induction of GADD34, a regulatory subunit of protein phosphatase-1 (PP1c), which dephosphorylates eIF2␣-P. H2S leads to increased eIF2␣-P levels by inhibiting PP1c phosphatase via persulfidation, which in turn leads to transient suppression of global translation and activation of ATF4 expression
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