RRC ID 53480
Author Nakamura S, Karalay Ö, Jäger PS, Horikawa M, Klein C, Nakamura K, Latza C, Templer SE, Dieterich C, Antebi A.
Title Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals.
Journal Nat Commun
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.
Volume 7
Pages 10944
Published 2016-3-22
DOI 10.1038/ncomms10944
PII ncomms10944
PMID 27001890
PMC PMC4804169
MeSH 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*
IF 12.121
Times Cited 24
C.elegans tm1516 tm1978 tm311 tm1530 tm420