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

Shuhei Nakamura, Özlem Karalay, Philipp S. Jäger, Makoto Horikawa, Corinna Klein, Kayo Nakamura, Christian Latza, Sven E. Templer, Christoph Dieterich and Adam Antebi ()
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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
Corinna Klein: Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, 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
Adam Antebi: Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, Cologne 50931, Germany

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10944

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