An mTORC2-Lipid Signaling Axis Controls Stress-Induced Organismal Death.

mTORC2 signaling plays a central role in regulating growth and survival under both physiological and stress conditions. Unlike mTORC1, however, the mechanisms by which mTORC2 integrates external nutrition or stress signals to coordinate internal metabolic homeostasis with organismal growth and survival remain poorly understood. Here, we find that mTORC2 signaling induces a decline in somatic lipid homeostasis, which in turn signals through a lipid/nuclear hormone receptor pathway that determines organismal survival or death following a severe cold stress (CS). CS disrupts somatic lipid homeostasis and induces rapid organismal death through apoptosis, a process we found to be promoted by mTORC2 and its downstream kinase SGK-1. Our study further identifies the sphingolipid metabolite sphingosine-1-phosphate (S1P) as a signal mediating cross-tissue communication from lipid stores. S1P signals to distant tissues, including neurons, to coordinate systemic decisions between organismal survival and death. S1P activates the nuclear receptor PPARα/NHR-49, which represses the expression of the acid sphingomyelinase ASM-3 to promote survival. In the absence of this repression, CS-induced secretion of ASM-3 induces neuronal damage and organismal death through apoptosis. Our findings define a lipid-based signaling pathway downstream of mTORC2 that couples external stress and metabolic state to the regulation of organismal survival.