In mammals, the TOR-TFEB axis is well known to regulate autophagy and lysosomal biogenesis. Recently, it has been shown by LaPierre et al that the C. elegans TFEB homolog HLH-30 is required for several known longevity pathways, and localizes to the nucleus in response to these signals. However, regulation of TFEB/HLH-30 and its interaction with other pathways in long-lived animals is not well understood. From a large-scale RNAi screen, we identified the Mondo-like transcription factor MML-1 and its heterodimer partner MXL-2 as a novel regulators of gonadal longevity. These factors regulate glucose metabolism and lipogenesis in mammals. We found that MML-1/MXL-2 were both required for longevity induced by glp-1 mutation or germline laser ablation. Consistent with a role in the gonadal longevity, nuclear MML-1::GFP was elevated upon germline loss, and overexpression of MML-1 modestly extended lifespan in the wild type. HLH-30 normally is nuclear localized in the glp-1 background. Surprisingly, we found that this nuclear localization was largely abolished by mml-1 and mxl-2 mutation. Accordingly, hlh-30 downstream events such as autophagy and lysososmal biogenesis were reduced in these mutants. HLH-30 localization and activity are also known to be regulated by TORC1. We found that phosphorylated S6 Kinase levels, a readout of TORC1 activity, became elevated upon mml-1 and mxl-2 deletion, suggesting that these factors regulate TOR signaling. In particular, we discovered that the amino acid sensor and TOR effector, leucyl-tRNA synthetase lars-1, was upregulated by mml-1 deletion. Knockdown of TORC1 components (TOR/let-363, raptor/daf-15 and raga-1) and lars-1 but not TORC2 specific component (rict-1) restored HLH-30 nuclear localization and target gene expression in the mml-1 and mxl-2 background. However, neither longevity nor autophagic process were fully rescued by lars-1 or TORC1 knockdown. Transcriptome analysis revealed substantial overlap between hlh-30 and mml-1 downstream target genes, but also identified mml-1 specific downstream genes that we implicated in longevity. Taken together, our analysis reveals that MML-1/MXL-2 regulates HLH-30 activity via TORC1 inhibition upon germline loss. Together these transcription factors cooperate in a coherent regulatory network governing autophagy, lysosomal biogenesis, and longevity.
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