Presentation/Session Information

Session Information

Session Title: Physiology: Aging and Stress I Session Type: Parallel
Session Location: Grand Horizon Ballroom Session Time: Thu, Jun 25 8:30AM - 11:30AM

Presentation Information

Program Number: 26 Presentation Time: 9:18AM - 9:30AM

Presentation Content

MML-1/Mondo complexes regulate HLH-30/TFEB via TOR inhibition to promote longevity in response to signals from the reproductive system.S. Nakamura 1, O. Karalay 1, P. Jaeger 1, M. Horikawa 1, K. Nakamura 1, C. Latza 1, C. Klein 1, S. Templer 1, C. Dieterich 1, A. Antebi 1,2,3. 1)Max Planck Institute for Biology of Ageing, Cologne, Germany; 2)Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, USA; 3)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

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.

Please note: Abstract shown here should NOT be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

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