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CGEF-1 regulates mTORC1 signaling during adult longevity and stress response in C. elegans

Yujie Li1, Sandra Finkbeiner1, Athina Ganner1

  • 1Department of Nephrology, Medical Center, University of Freiburg, Freiburg, Germany.

Oncotarget
|March 9, 2018
PubMed

Insights

Inhibition of CGEF-1 extends lifespan and stress resistance in C. elegans by modulating mechanistic target of rapamycin complex 1 (mTORC1) signaling. This conserved pathway involves RHEB-1 and impacts aging and disease.

Area of Science:

  • Cellular Biology
  • Aging Research
  • Molecular Genetics

Background:

  • The mechanistic target of rapamycin (mTOR) kinase is a key regulator of cell metabolism, growth, and aging.
  • mTOR functions in two complexes, mTORC1 and mTORC2, with mTORC1 inhibition linked to increased lifespan in various organisms.
  • mTORC1 signaling promotes protein synthesis and suppresses autophagy, processes critical for cellular homeostasis.

Purpose of the Study:

  • To identify novel regulators of mTORC1 signaling in C. elegans.
  • To investigate the role of CGEF-1, a homolog of human Dbl, in mTORC1 pathway regulation and its impact on aging.
  • To explore the evolutionary conservation of CGEF-1/Dbl function in mTORC1 signaling.

Main Methods:

  • Genetic screening in C. elegans to identify CGEF-1 as a binding partner of RHEB-1.
  • Lifespan and stress resistance assays in cgef-1 mutant worms.
  • Analysis of downstream mTORC1 targets, including 4E-BP phosphorylation and autophagy levels.
  • Investigating the role of transcription factors DAF-16/FoxO and SKN-1/Nrf.
  • Experiments in human cells to confirm the conserved function of Dbl.

Main Results:

  • CGEF-1 acts as a novel activator of mTORC1 signaling in C. elegans by binding to RHEB-1.
  • cgef-1 mutants exhibit significantly prolonged lifespan and enhanced resistance to stress.
  • The longevity and stress tolerance in cgef-1 mutants depend on DAF-16/FoxO and SKN-1/Nrf.
  • Inactivation of cgef-1 leads to reduced 4E-BP phosphorylation and increased autophagy.
  • Human Dbl protein associates with Rheb and activates mTORC1 signaling, indicating evolutionary conservation.

Conclusions:

  • CGEF-1 is a conserved activator of mTORC1 signaling, regulating lifespan and stress resistance in C. elegans.
  • The findings elucidate a novel mechanism of mTORC1 regulation with implications for understanding aging and age-related diseases.
  • Targeting the CGEF-1/Dbl-Rheb-mTORC1 axis could offer therapeutic strategies for age-related conditions.
Keywords:
C. elegansRhebagingmTORC1 signalingstress response

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