H2S signalling through protein sulfhydration and beyond

Hydrogen sulfide (H2S) has emerged as an important gasotransmitter and signalling molecule, akin to nitric oxide (NO) and carbon monoxide (CO).H2S is generated from Cys and its derivatives by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MST).H2S has a major role in vasorelaxation and regulation of blood pressure. Mice lacking CSE display substantial cardiovascular dysfunction and hypertension.One of the mechanisms by which H2S mediates its effects is via protein sulfhydration, which is analogous to nitrosylation by NO. In the process of sulfhydration, the thiol group of a reactive Cys is modified to an persulfide (-SSH) group, resulting in increased reactivity of the Cys residue. Sulfhydration is more prevalent than nitrosylation, as 25–50% of murine hepatic proteins were found to be sulfhydrated.Sulfhydration orchestrates diverse signalling pathways ranging from vasorelaxation to the stress response. The vasoactivity of H2S stems from its ability to sulfhydrate the Kir6.1 subunit of ATP-dependent potassium (KATP) channels to elicit hyperpolarization of vascular smooth muscle cells.H2S regulates the endoplasmic reticulum (ER) stress response by sulfhydrating and inhibiting protein Tyr phosphatase 1B (PTP1B), a key player in the ER stress response pathway. H2S also mediates the anti-apoptotic activity of nuclear factor-κB (NF-κB) by sulfhydrating the p65 subunit, thereby augmenting the transcription of pro-survival genes.Sulfhydration is a reversible event, a feature that is necessary for the dynamic regulation of signalling pathways.Sulhydration and nitrosylation may interface to modulate cellular responses. In the case of stress signalling by NF-κB, sulfhydration of Cys38 precedes its nitrosylation, providing a mechanistic basis for differentiating cell survival from cell death.