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Nat Commun. 2016 Mar 22;7:10944. doi: 10.1038/ncomms10944.

Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals.

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Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
Computational RNA Biology and Ageing, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.


Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival.

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