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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Germ Cells / metabolism
  • Gonads / metabolism*
  • Longevity*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Transport
  • Reproduction
  • Signal Transduction*
  • Trans-Activators / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Caenorhabditis elegans Proteins
  • HLH-30 protein, C elegans
  • MML-1 protein, C elegans
  • MXL-2 protein, C elegans
  • Trans-Activators
  • Phosphotransferases (Alcohol Group Acceptor)
  • let-363 protein, C elegans