title: Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals.
abstract: 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.
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Karalay
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Jäger
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Makoto
authors.initials: M
authors.lastname: Horikawa
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Klein
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Kayo
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Latza
authors.affiliation: Computational RNA Biology and Ageing, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
authors.forename: Sven E
authors.initials: SE
authors.lastname: Templer
authors.affiliation: Computational RNA Biology and Ageing, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, 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.
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
mesh_terms: D000818:Animals; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005854:Germ Cells / Q000378:metabolism; D006066:Gonads / Q000378:metabolism*; D008136:Longevity; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D021381:Protein Transport; D012098:Reproduction; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D015534:Trans-Activators; C583069:HLH-30 protein, C elegans; C525397:MML-1 protein, C elegans; C525398:MXL-2 protein, C elegans; C472494:let-363 protein, C elegans