Hypoxia alters eating behavior in different animals. In C. elegans , hypoxia induces a strong food leaving response. We found that this behavior was independent of the known O 2 response mechanisms including acute O 2 sensation and HIF-1 signaling of chronic hypoxia response. Mutating egl-3 and egl-21 , encoding the neuropeptide pro-protein convertase and carboxypeptidase, led to defects in hypoxia induced food leaving, suggesting that neuropeptidergic signaling was required for this response. However, we failed to identify any neuropeptide mutants that were severely defective in hypoxia induced food leaving, suggesting that multiple neuropeptides act redundantly to modulate this behavior.

Aberrant cytokine secretion contributes to the pathogenesis of autoimmune diseases and age-related disorders, but the molecular mechanism underlying this is not entirely clear. Here, we elucidate how interleukin-17 (IL-17) overactivation shortens lifespan and damages defense mechanisms against stress in C. elegans. Our analysis reveals that NHR-49, the C. elegans ortholog of human PPARα and HNF4, is the central component in the transcriptional network undermined by increased IL-17 signaling. Both NHR-49 and its coactivator MDT-15 physically interact with the downstream components of IL-17 pathway, and their expression is significantly decreased when IL-17 signaling is enhanced. IL-17 overactivation also induces the expression and nucleus entry of the C. elegans ortholog of NF-κB inhibitor NFKI-1/IκBζ to repress the activity of transcriptional coactivator MDT-15 and CBP-1. IL-17 signaling acts on neurons to modulate the activity of NFKI-1/IκBζ and NHR-49. In addition, persistent IL-17 activation decreases the expression of HLH-30/TFEB, leading to the reduced transcription of lysosomal lipase genes in the distal tissues. All these jointly contribute to the increased sensitivity to oxidative stress of animals with enhanced IL-17 signaling. Collectively, our work illustrates a transcription system undermined by IL-17 overactivation in the animals without NF-κB, and provides mechanistic insight into the pathogenesis of abnormal IL-17 secretion.