A genetic program mediates cold-warming response and promotes stress-induced phenoptosis in .

How multicellular organisms respond to and are impacted by severe hypothermic stress is largely unknown. From screens for mutants abnormally responding to cold-warming stimuli, we identify a molecular genetic pathway comprising ISY-1, a conserved uncharacterized protein, and ZIP-10, a bZIP-type transcription factor. ISY-1 gatekeeps the ZIP-10 transcriptional program by regulating the microRNA . Downstream of ISY-1 and , levels rapidly and specifically increase upon transient cold-warming exposure. Prolonged up-regulation induces several protease-encoding genes and promotes stress-induced organismic death, or phenoptosis, of . deficiency confers enhanced resistance to prolonged cold-warming stress, more prominently in adults than larvae. We conclude that the ZIP-10 genetic program mediates cold-warming response and may have evolved to promote wild-population kin selection under resource-limiting and thermal stress conditions.