The target of rapamycin (TOR) kinase coordinately regulates fundamental metabolic and cellular processes to support growth, proliferation, survival, and differentiation, and consequently it has been proposed as a therapeutic target for the treatment of cancer, metabolic disease, and aging. The TOR kinase is found in two biochemically and functionally distinct complexes, termed TORC1 and TORC2. Aided by the compound rapamycin, which specifically inhibits TORC1, the role of TORC1 in regulating translation and cellular growth has been extensively studied. The physiological roles of TORC2 have remained largely elusive due to the lack of pharmacological inhibitors and its genetic lethality in mammals. Among potential targets of TORC2, the pro-survival kinase AKT has garnered much attention. Within the context of intact animals, however, the physiological consequences of phosphorylation of AKT by TORC2 remain poorly understood. Here we describe viable loss-of-function mutants in the Caenorhabditis elegans homolog of the TORC2-specific component, Rictor (CeRictor). These mutants display a mild developmental delay and decreased body size, but have increased lipid storage. These functions of CeRictor are not mediated through the regulation of AKT kinases or their major downstream target, the insulin-regulated FOXO transcription factor DAF-16. We found that loss of sgk-1, a homolog of the serum- and glucocorticoid-induced kinase, mimics the developmental, growth, and metabolic phenotypes of CeRictor mutants, while a novel, gain-of-function mutation in sgk-1 suppresses these phenotypes, indicating that SGK-1 is a mediator of CeRictor activity. These findings identify new physiological roles for TORC2, mediated by SGK, in regulation of C. elegans lipid accumulation and growth, and they challenge the notion that AKT is the primary effector of TORC2 function.
The target of rapamycin (TOR) kinase acts as a conserved sensor of energy status and governs diverse functions such as metabolism, growth, and cell size via two separate multiprotein complexes. TOR complex 1 (TORC1), which is sensitive to the immunosuppressant drug rapamycin, is well understood but the physiological roles and molecular mechanisms of action of the second TOR complex (TORC2) are not so clear. We describe mutants in the single Caenorhabditis elegans homolog of the gene Rictor, which is the defining component of the TORC2 signaling complex. Mutant worms are small, developmentally delayed, have reduced fecundity, and store more fat than wild-type C. elegans does. Akt kinases, which are pro-survival kinases that mediate the effects of insulin and other growth factors, have been postulated to be key mediators of TORC2 signaling, as they are targets of TORC2 phosphorylation. We find, however, that in C. elegans, TORC2 regulates fat storage, size, and development entirely independent of the Akt kinases and of the major target of insulin signaling, the FOXO-family transcription factor DAF-16. Instead, we show genetically that TORC2 acts through the activation of SGK-1, a kinase closely related to Akt, to govern all three phenotypes. This work indicates a role for TORC2 in fat regulation and shows that SGK-1 is a physiologically significant mediator of TORC2 signaling.
C. elegans TOR complex 2 regulates lipid storage, body size, and development through downstream activation of the SGK-1 kinase, independent of AKT kinases and of the DAF-16/FOXO transcription factor.