A Novel Mechanism To Prevent H2S Toxicity in Caenorhabditis elegans

Hydrogen sulfide (H 2 S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, H 2 S is also toxic, and unregulated accumulation or exposure to environmental H 2 S can be lethal. In Caenorhabditis elegans , the hypoxia inducible factor ( hif-1 ) coordinates the initial transcriptional response to H 2 S, and is essential to survive exposure to low concentrations of H 2 S. We performed a forward genetic screen to identify mutations that suppress the lethality of hif-1 mutant animals in H 2 S. The mutations we recovered are specific for H 2 S, 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 H 2 S-responsive genes, consistent with previous findings that skn-1 plays a role in the transcriptional response to H 2 S. Using transgenic rescue, we show that overexpression of a single gene, rhy-1 , is sufficient to protect hif-1 mutant animals in H 2 S. 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 H 2 S.