C. elegans RHY-1 and CYSL-1 act independently of HIF-1 to promote survival in hydrogen sulfide

Hydrogen sulfide (H 2 S) is an endogenously produced signaling molecule that can be cytoprotective, especially in conditions of ischemia/reperfusion injury. However, exposure to exogenous H 2 S can be toxic, perhaps due to unregulated activation of endogenous H 2 S signaling pathways. We use the nematode C. elegans to define mechanisms that mediate the physiological effects of H 2 S in animals. We have previously shown that in C. 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. In this study, 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 do not suppress embryonic lethality or reproductive arrest of hif-1 mutant animals in hypoxia, nor can they improve viability of hif-1 mutant animals exposed to hydrogen cyanide, indicating that these are specific for H 2 S. We found that the hif-1 suppressor mutations 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 our previous finding that skn-1 plays a role in the transcriptional response to H 2 S. Using transgenic rescue, we show a single gene, rhy-1 , alone is sufficient to protect hif-1 mutant animals in H 2 S. Our data indicate that RHY-1 acts in concert with CYSL-1, an orthologue of human cystathionine β-synthase, to promote survival 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 studies reveal a novel function of RHY-1, which is independent of hif-1 , that protects against toxic effects of H 2 S.