Caenorhabditis elegans OSM-11 signaling regulates SKN-1/Nrf during embryonic development and adult longevity and stress response.

The Nrf family of transcription factors is critical for stress defense and detoxification. In Caenorhabditis elegans, the Nrf protein ortholog SKN-1 mediates this conserved stress response and promotes longevity. Moreover, SKN-1 is well known for its essential functions during C. elegans embryogenesis. SKN-1 is maternally deployed and initiates a signaling network specifying development of the endoderm and mesoderm. In this study, we identify the conserved Notch ligand OSM-11 as a novel regulator of SKN-1. We find that genetic inactivation of osm-11 re-establishes development of the pharynx and intestine in skn-1 deficient embryos and thereby rescues embryonic lethality associated with loss of skn-1 function. Inactivation of other DSL- and DOS-motif Notch ligands does not prevent skn-1 embryonic lethality. In addition, we show that inactivation of osm-11 in adult worms robustly enhances lifespan and promotes resistance to environmental stress. SKN-1 is required for increased longevity and heat and oxidative stress resistance but not hyperosmotic stress conferred by osm-11. OSM-11 prevents the nuclear accumulation of SKN-1 and represses the transcriptional activation of SKN-1 target genes for cellular detoxification. Our findings indicate that OSM-11 antagonizes SKN-1 during embryonic development and reveal a highly context-specific relationship between OSM-11 and SKN-1 in promoting stress resistance and longevity.