Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Yujie Li _, Sandra Finkbeiner, Athina Ganner, Julia Gerber, Marinella Klein, Manuel Grafe, Jakob Kandzia, Antje Thien, Kathrin Thedieck, Gerhard Breves, Thomas Jank, Ralf Baumeister, Gerd Walz, Elke Neumann- Haefelin

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Oncotarget. 2018; 9:9581-9595. https://doi.org/10.18632/oncotarget.24039

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Abstract

Yujie Li1,*, Sandra Finkbeiner1,*, Athina Ganner1, Julia Gerber1,9, Marinella Klein1, Manuel Grafe1, Jakob Kandzia1, Antje Thien1,2, Kathrin Thedieck2,3,4, Gerhard Breves9, Thomas Jank5, Ralf Baumeister2,6,7,8, Gerd Walz1,6 and Elke Neumann-Haefelin1

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

2Bioinformatics and Molecular Genetics, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany

3Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

4Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany

5Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany

6Centre for Biological Signaling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany

7Centre for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, Freiburg, Germany

8ZBMZ Centre for Biochemistry and Molecular Cell Research, Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany

9Department of Physiology, University of Veterinary Medicine Hannover, Hannover, Germany

*These authors contributed equally to this work

Correspondence to:

Neumann-Haefelin, email: elke.neumann-haefelin@uniklinik-freiburg.de

Keywords: mTORC1 signaling; Rheb; aging; stress response; C. elegans

Received: September 30, 2017     Accepted: November 15, 2017     Published: January 06, 2018

ABSTRACT

The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this study, we demonstrate that CGEF-1, the C. elegans homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in C. elegans. cgef-1 mutants display prolonged lifespan and enhanced stress resistance. The transcription factors DAF-16/FoxO and SKN-1/Nrf are required for increased longevity and stress tolerance, and induce protective gene expression in cgef-1 mutants. Genetic evidence indicates that cgef-1 functions in the same pathway with rheb-1, the mTOR kinase let-363, and daf-15/Raptor. When cgef-1 is inactivated, phosphorylation of 4E-BP, a central mTORC1 substrate for protein translation is reduced in C. elegans. Moreover, autophagy is increased upon cgef-1 and mTORC1 inhibition. In addition, we show that in human cells Dbl associates with Rheb and stimulates mTORC1 downstream targets for protein synthesis suggesting that the function of CGEF-1/Dbl in the mTORC1 signaling pathway is evolutionarily conserved. These findings have important implications for mTOR functions and signaling mechanisms in aging and age-related diseases.


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