LAUSR

How an organism dies is a fundamental yet poorly understood question in biology. An organism can die of many causes, including stress‐induced phenoptosis, also defined as organismic death that is regulated by its genome‐encoded programs. The mechanism of stress‐induced phenoptosis is still largely unknown. Here, we show that transient but severe freezing‐thaw stress (FTS) in Caenorhabditis elegans induces rapid and robust phenoptosis that is regulated by G‐protein coupled receptor (GPCR) signaling. RNAi screens identify the GPCR‐encoding fshr‐1 in mediating transcriptional responses to FTS. FSHR‐1 increases ligand interaction upon FTS and activates a cyclic AMP‐PKA cascade leading to a genetic program to promote organismic death under severe stress. FSHR‐1/GPCR signaling up‐regulates the bZIP‐type transcription factor ZIP‐10, linking FTS to expression of genes involved in lipid remodeling, proteostasis, and aging. A mathematical model suggests how genes may promote organismic death under severe stress conditions, potentially benefiting growth of the clonal population with individuals less stressed and more reproductively privileged. Our studies reveal the roles of FSHR‐1/GPCR‐mediated signaling in stress‐induced gene expression and phenoptosis in C. elegans, providing empirical new insights into mechanisms of stress‐induced phenoptosis with evolutionary implications.