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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.

SUBMITTER: Nakamura S 

PROVIDER: S-EPMC4804169 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Nakamura Shuhei S   Karalay Özlem Ö   Jäger Philipp S PS   Horikawa Makoto M   Klein Corinna C   Nakamura Kayo K   Latza Christian C   Templer Sven E SE   Dieterich Christoph C   Antebi Adam A  

Nature communications 20160322


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. Germl  ...[more]

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