The Response of Caenorhabditis elegans to Hydrogen Sulfide and Hydrogen Cyanide

Hydrogen sulfide (H(2)S), an endogenously produced small molecule, protects animals from various stresses. Recent studies demonstrate that animals exposed to H(2)S are long lived, resistant to hypoxia, and resistant to ischemia–reperfusion injury. We performed a forward genetic screen to gain insights into the molecular mechanisms Caenorhabditis elegans uses to appropriately respond to H(2)S. At least two distinct pathways appear to be important for this response, including the H(2)S-oxidation pathway and the hydrogen cyanide (HCN)-assimilation pathway. The H(2)S-oxidation pathway requires two distinct enzymes important for the oxidation of H(2)S: the sulfide:quinone reductase sqrd-1 and the dioxygenase ethe-1. The HCN-assimilation pathway requires the cysteine synthase homologs cysl-1 and cysl-2. A low dose of either H(2)S or HCN can activate hypoxia-inducible factor 1 (HIF-1), which is required for C. elegans to respond to either gas. sqrd-1 and cysl-2 represent the entry points in the H(2)S-oxidation and HCN-assimilation pathways, respectively, and expression of both of these enzymes is highly induced by HIF-1 in response to both H(2)S and HCN. In addition to their role in appropriately responding to H(2)S and HCN, we found that cysl-1 and cysl-2 are both essential mediators of innate immunity against fast paralytic killing by Pseudomonas. Furthermore, in agreement with these data, we showed that growing worms in the presence of H(2)S is sufficient to confer resistance to Pseudomonas fast paralytic killing. Our results suggest the hypoxia-independent hif-1 response in C. elegans evolved to respond to the naturally occurring small molecules H(2)S and HCN.