TBC-2, a Rab GTPase activating protein, regulates the localization of the HLH-30/TFEB and PQM-1 transcription factors in the C. elegans intestine
Abstract
Insulin/IGF signaling (IIS) inhibits the nuclear localization of the DAF-16/FOXO transcription factor to regulate longevity and stress resistance in C. elegans. In the intestine, IIS promotes DAF-16 localization to endosomes and loss of TBC-2, a RAB-5 GAP, results in increased endomembrane localization of DAF-16 at the expense of nuclear localization, decreased DAF-16 target gene expression, longevity and stress resistance. Here we found that TBC-2 differentially regulates the localization of the IIS-regulated transcription factors PQM-1 and HLH-30/TFEB. Our results suggest a broader role for TBC-2 in negatively regulating IIS and that TBC-2 likely functions at an upstream point in the IIS pathway.
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Research summary
TBC-2 regulates the differential subcellular localization of transcription factors HLH-30/TFEB and PQM-1 in response to insulin/IGF signaling, thereby modulating longevity and stress resistance in C. elegans. This study provides incremental mechanistic detail on known pathways (IIS, FOXO/DAF-16, TFEB) without offering surprising new paradigms or significant therapeutic implications for human aging.
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