The Rab GTPase activating protein TBC-2 extends longevity by facilitating release of FOXO/DAF-16 from endosomes

Abstract

FOXO transcription factors have been shown to regulate longevity in model organisms and are associated with longevity in humans. To gain insight into how FOXO functions to increase lifespan, we examined the subcellular localization of DAF-16 in C. elegans. We show that DAF-16 is localized to endosomes and that this endosomal localization is increased by the insulin-IGF signaling (IIS) pathway. Endosomal localization of DAF-16 is also increased by disrupting the Rab GTPase activating protein TBC-2, or decreased by inhibiting the RAB-5 or RAB-7 GTPases, key regulators of early to late endosome maturation. Importantly, the amount of DAF-16 that is localized to endosomes has functional consequences as increasing endosomal localization through mutations in tbc-2 decreased the lifespan of long-lived daf-2 IGFR mutants, depleted their fat stores, and DAF-16 target gene expression. Finally, we show that the ability of TBC-2 proteins, TBC1D2 and TBC1D2B, to regulate FOXO protein localization is conserved in human cells. Overall, this work identifies endosomal localization as a mechanism regulating FOXO/DAF-16, which is important for its functions in metabolism and aging.