Sphingosine kinase and p38 MAP kinase signaling promote resistance to arsenite-induced lethality in Caenorhabditis elegan

Backgrounds Arsenite is a naturally occurring mitochondrial toxin that generates oxidative stress in vivo. Previously, we have reported that SPHK-1/sphingosine kinase plays a critical role in promoting survival following arsenite exposure in C. elegans. However, the molecular mechanism by which SPHK-1 confers resistance to arsenite-induced toxicity is not known. Methods Using a combination of genetic, fluorescence imaging, and behavioral approaches, we addressed the cellular and molecular mechanism by which SPHK-1 signaling protects animals from arsenite-induced lethality. Results SPHK-1 kinase activity and localization to mitochondria are required for protection from arsenite-induced lethality. Genetic alterations leading to low SPH levels promote resistance to arsenite-mediated toxicity. SPHK-1 functions in the PMK-1/p38 MAPK pathways in the intestine to promote protection. Finally, sphk-1 mutants are sensitive to a range of oxidative stressors including juglone, paraquat and heat. Conclusion SPHK-1 and PMK-1 signaling play important roles in the oxidative stress response in C. elegans.