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

Author

Listed:
  • Shuhei Nakamura

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany)

  • Özlem Karalay

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany)

  • Philipp S. Jäger

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany)

  • Makoto Horikawa

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany
    Present address: Hamamatsu University School of Medicine, Department of Cell Biology and Anatomy, 1-20-1 Handayama, Higashi-ku, Hamamatsu city, Shizuoka 431-3192, Japan)

  • Corinna Klein

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany
    Present address: CECAD Research Center, Lipidomics & Proteomics Facility, Joseph-Stelzmann-Str. 26, Cologne 50931, Germany)

  • Kayo Nakamura

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany)

  • Christian Latza

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany)

  • Sven E. Templer

    (Computational RNA Biology and Ageing, Max Planck Institute for Biology of Ageing)

  • Christoph Dieterich

    (Computational RNA Biology and Ageing, Max Planck Institute for Biology of Ageing
    Present address: Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III, Klaus Tschira Institute for Computational Cardiology, University Hospital Heidelberg, Heidelberg 69120, Germany)

  • Adam Antebi

    (Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany
    Huffington Center on Aging, Baylor College of Medicine
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne)

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.

Suggested Citation

  • Shuhei Nakamura & Özlem Karalay & Philipp S. Jäger & Makoto Horikawa & Corinna Klein & Kayo Nakamura & Christian Latza & Sven E. Templer & Christoph Dieterich & Adam Antebi, 2016. "Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10944
    DOI: 10.1038/ncomms10944
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    Cited by:

    1. Elite Possik & Laura-Lee Klein & Perla Sanjab & Ruyuan Zhu & Laurence Côté & Ying Bai & Dongwei Zhang & Howard Sun & Anfal Al-Mass & Abel Oppong & Rasheed Ahmad & Alex Parker & S.R. Murthy Madiraju & , 2023. "Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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