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

During metazoan development, how cell division and metabolic programs are coordinated with nutrient availability remains unclear. Here, we show that nutrient availability signaled by the neuronal cytokine, ILC-17.1 switchesC. elegansdevelopment between reproductive growth and dormancy by controlling the activity of the tumor suppressor p53 ortholog, CEP-1. Specifically, upon food availability, ILC-17.1 signaling by amphid neurons promotes glucose utilization and suppresses CEP-1/p53 to allow growth. In the absence of ILC-17.1, CEP-1/p53 is activated, upregulates cell-cycle inhibitors, decreases phosphofructokinase and cytochrome C expression, and causes larvae to arrest as stress-resistant, quiescent dauers. We propose a model whereby ILC-17.1 signaling links nutrient availability and energy metabolism to cell cycle progression through CEP-1/p53. These studies describe ancestral functions of IL-17s and the p53-family of proteins and are relevant to our understanding of neuroimmune mechanisms in cancer. They also reveal a DNA damage-independent function of CEP-1/p53 in invertebrate development and support the existence of a previously undescribedC. elegansdauer pathway.

During metazoan development, nutrient availability is coordinated with the division, growth and metabolic activity of individual cells through cell-cell communication. This is also the case in the invertebrateC. elegans, a free-living bacterivore, which displays a dramatic developmental plasticity to ensure that its growth and reproduction match available resources(1–10). WhenC. eleganslarvae hatch under optimal conditions (at 20°C, low population densities, on abundant food) they develop continuously into reproducing adults. However, if they hatch under suboptimal conditions, such as in the paucity of food, at high population densities, or high ambient temperatures, larvae implement an alternative developmental program and arrest as quiescent, stress-resistant larvae called ‘dauer‘ larvae. Dauer larvae display metabolic and organismal phenotypes specialized for dispersal and survival, and can remain arrested in this state for months to resume development into reproductive adults when favorable conditions return(1–10). Previous studies have identified molecular pathways that mediate the dauer decision, showing that growth promoting molecules like insulins, transforming β growth factor (TGFβ/DAF-7) and lipid based dafachronic acid hormones are released by sensory neurons and other cells to license continued development; adverse environments inhibit these growth promoting signals and trigger dauer arrest(1–11). A number of quantitative trait loci (QTL) also modulate dauer (12). Yet, how the dauer entry decision results in a coordinated change in cell fates across different tissues and is linked with the systemic shut-down of anabolic pathways remains poorly understood.

An important group of proteins that mediate cell-cell communication and metabolism in metazoa are secreted proteins called cytokines(13, 14). The IL-17 cytokines constitute a family of proinflammatory cytokines, highly conserved across animal phyla. In mammals, these cytokines are released by specialized immune cells to activate immune surveillance, enhance barrier function, promote wound healing, and play crucial immunometabolic roles in maintaining energy homeostasis(15). In humans, IL-17s also promote cancers and autoimmune disease such as psoriasis(16, 17). Here, we show that theC. elegansIL-17 ortholog, ILC-17.1, signals food availability, and coordinates cell division with metabolism by controlling the activity of theC. eleganstumor suppressor p53 ortholog, CEP-1. Specifically, neuronal ILC-17.1 suppresses CEP-1/p53 activity in the presence of food to license growth. Upon the loss of ILC-17.1 signaling, CEP-1/p53 is activated, and remarkably, this switches whole organism development from continuous growth to dormancy. The p53-like tumor suppressor genes are found in all multicellular animals where they prevent the transmission of damaged DNA by activating a multifaceted program that controls cell cycle checkpoints, mediates reversible growth arrest or apoptosis, and controls metabolic flux (18–22). Our studies show that these functions of CEP-1/p53 also act, in the absence of DNA damage, to control developmental quiescence ofC. elegans, suggesting that the developmental function of the p53-gene family could have shaped their evolution(23–25).