kri-1/KRIT1 restrains skn-1/NRF2 activation to promote innate immune and lipid homeostasis

Animals must differentially allocate essential metabolic resources in response to changing environmental conditions to ensure reproductive success. For example, adult C. elegans coordinate innate immune defenses during infection and also allocate fat stores to the germline, each of which are required for evolutionary fitness. The genetic mechanisms that integrate resource allocation and host defenses in this context, however, are not fully understood. From a forward genetic screen for novel regulators of innate immune gene transcription, we identified kri-1, the nematode homolog of human Krev interaction trapped protein KRIT1. Mutations in human KRIT1 underlie cerebral cavernous malformations, a disease marked by defects in vascular integrity. Similarly, C. elegans kri-1/KRIT1 is required for the integrity of the intestinal epithelial cell barrier. We find also that kri-1/KRIT1 is required for host tolerance to bacterial infection, fecundity, and normal development. In this context, kri-1/KRIT1 restrains the activity of the cytoprotective transcription factor skn-1/NRF2 to control immune gene transcription and intestinal lipid mobilization during aging, a process necessary for healthy reproduction, but functions independently of skn-1/NRF2 to promote epithelial integrity and pathogen tolerance. These data reveal a broad role for a strongly conserved regulator in essential physiological processes that are required for reproductive fidelity and evolutionary success.