A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans.

Hydrogen sulfide (H₂S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, H₂S is also toxic, and unregulated accumulation or exposure to environmental H₂S can be lethal. In C. elegans the hypoxia inducible factor (hif-1) coordinates the initial transcriptional response to H₂S and is essential to survive exposure to low concentrations of H₂S. We performed a forward genetic screen to identify mutations that suppress the lethality of hif-1 mutant animals in H₂S. The mutations we recovered are specific for H₂S, as they do not suppress embryonic lethality or reproductive arrest of hif-1 mutant animals in hypoxia, nor can they prevent the death of hif-1 mutant animals exposed to hydrogen cyanide. The majority of hif-1 suppressor mutations we recovered activate the skn-1/Nrf2 transcription factor. Activation of SKN-1 by hif-1 suppressor mutations increased the expression of a subset of H₂S-responsive genes, consistent with previous findings that skn-1 plays a role in the transcriptional response to H₂S. Using transgenic rescue, we show that overexpression of a single gene, rhy-1, is sufficient to protect hif-1 mutant animals in H₂S. The rhy-1 gene encodes a predicated O-acyltransferase enzyme that has previously been shown to negatively regulate HIF-1 activity. Our data indicate that RHY-1 has novel, hif-1 independent, function that promotes survival in H₂S.