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

• Published in: Oncotarget 2018-02, Vol.9 (11), p.9581-9595
• Main Authors: Li, Yujie, Finkbeiner, Sandra, Ganner, Athina, Gerber, Julia, Klein, Marinella, Grafe, Manuel, Kandzia, Jakob, Thien, Antje, Thedieck, Kathrin, Breves, Gerhard, Jank, Thomas, Baumeister, Ralf, Walz, Gerd, Neumann-Haefelin, Elke
• Format: Article
• Language: English
• Subjects: Research Paper: Gerotarget(Focus on Aging)
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.24039

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 homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in . 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 mutants. Genetic evidence indicates that functions in the same pathway with , the mTOR kinase , and /Raptor. When is inactivated, phosphorylation of 4E-BP, a central mTORC1 substrate for protein translation is reduced in . Moreover, autophagy is increased upon 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.