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

// Yujie Li 1, * , Sandra Finkbeiner 1, * , Athina Ganner 1 , Julia Gerber 1, 9 , Marinella Klein 1 , Manuel Grafe 1 , Jakob Kandzia 1 , Antje Thien 1, 2 , Kathrin Thedieck 2, 3, 4 , Gerhard Breves 9 , Thomas Jank 5 , Ralf Baumeister 2, 6, 7, 8 , Gerd Walz 1, 6 and Elke Neumann-Haefelin 1 1 Department of Nephrology, Medical Center, University of Freiburg, Freiburg, Germany 2 Bioinformatics and Molecular Genetics, Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany 3 Department of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4 Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany 5 Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany 6 Centre for Biological Signaling Studies (BIOSS), Albert-Ludwigs-University of Freiburg, Freiburg, Germany 7 Centre for Biological Systems Analysis (ZBSA), Albert-Ludwigs-University Freiburg, Freiburg, Germany 8 ZBMZ Centre for Biochemistry and Molecular Cell Research, Faculty of Medicine, Albert-Ludwigs-University Freiburg, Freiburg, Germany 9 Department 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.