A Novel Mechanism To Prevent HS Toxicity in .

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