Stress-induced organismal death is genetically regulated by the mTOR–Zeste–Phae1 axis

All organisms are exposed to various stressors, which can sometimes lead to organismal death, depending on their intensity. While stress-induced organismal death has been observed in many species, the underlying mechanisms remain unclear. In this study, we investigated the molecular mechanisms of stress-induced organismal death in the fruit fly <i>Drosophila melanogaster</i>. We identified a chymotrypsin-like serine protease <i>Phaedra1</i> (<i>Phae1</i>) as a death mediator in <i>D. melanogaster</i> larvae. <i>Phae1</i> expression was up-regulated by lethal heat stress (40 °C) but not nonlethal heat stress (38 °C or lower). The most prominent induction of <i>Phae1</i> occurred in the central nervous system (CNS). We found neuro-specific knockdown of <i>Phae1</i> increased survival and reduced neuronal caspase activity following exposure to lethal heat stress, suggesting that the transcriptional upregulation of <i>Phae1</i> in the CNS is essential for stress-induced organismal death. We next found via bioinformatic and biochemical analyses that the transcription factor Zeste (Z) bound the <i>Phae1</i> enhancer region and that <i>z</i> loss-of-function impaired <i>Phae1</i> induction in the CNS, increasing survival following lethal heat stress. In addition, we found via chemical screening that rapamycin, a chemical inhibitor of mechanistic target of rapamycin (mTOR), suppressed <i>Phae1</i> expression. Neuro-specific knockdown of <i>mTor</i> reduced the protein levels of both Phae1 and Z, leading to an increase in survival following lethal heat stress. Together, these results indicate that heat stress-induced organismal death in <i>D. melanogaster</i> larvae is regulated by a genetically encoded transcriptional signaling pathway involving the mTOR-Z-Phae1 axis.