Neuronal IL-17 controlsC. elegansdevelopmental diapause through p53/CEP-1

Abstract

AbstractMetazoan growth and development requires the coordination of cell cycle progression and metabolism with nutrient availability1–3. Here, we show that inC. elegans, amphid neurons regulate the animals’ developmental decision to continue reproductive growth or arrest as quiescent dauer larvae in response to food, by controlling the activity ofC. elegansp53-like ortholog, CEP-1. Specifically, upon food availability, larval neurons secrete a mammalian IL-17 ortholog, ILC-17.1, and ILC-17.1 signaling is needed forC. elegansto progress through development into reproductive adults. ILC-17.1 deficiency activates CEP-1/p53 in larval blast cells, and causes larvae to arrest as stress-resistant, quiescent dauers by activating DAF-16/FOXO, decreasing cytochrome C levels, decreasing glucose utilization, and upregulating cell cycle inhibitors. Increasing ILC-17.1 levels represses CEP-1/p53 and promotes anabolic growth, but also inhibits apoptosis upon genotoxic stress. IL-17 also represses p53 in human epithelial cells. These studies describe a role for the tumor suppressor p53-like proteins in controlling developmental quiescence of a metazoan in response to neuronal activity and immunometabolic signals and are relevant to our understanding of neuroimmune mechanisms in cancer. This novel role for p53-like proteins inC. eleganssupports the argument that their developmental function was a main driving force in their evolution4,5.