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Metabolic Stress Controls mTORC1 Lysosomal Localization and Dimerization by Regulating the TTT-RUVBL1/2 Complex

Kim, SG and Hoffman, GR and Poulogiannis, G and Buel, GR and Jang, YJ and Lee, KW and Kim, B and Erikson, RL and Cantley, LC and Choo, AY and Blenis, J (2013) Metabolic Stress Controls mTORC1 Lysosomal Localization and Dimerization by Regulating the TTT-RUVBL1/2 Complex. MOLECULAR CELL. pp. 172-185.

Abstract

The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC1/2-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL1/2 complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function-all mTORC1-regulated processes. Thus, the TTT-RUVBL1/2 complex responds to the cell's metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1. 2013 Elsevier Inc

Item Type: Article
Additional Information: pubid: 145 nvp_institute: NIBR contributor_address: (Kim, Hoffman, Buel, Jang, Choo, Blenis) Department of Cell Biology, Harvard Medical School, Boston, MA 02115, United States (Poulogiannis, Cantley) Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States (Jang, Lee) Department of Agricultural Biotechnology, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-921, South Korea (Kim) Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, 685-1 Yangcheonri, Ochangeup, Cheongwongun 363-883, South Korea (Erikson) Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, United States (Hoffman) Novartis Institutes for Biomedical Research, Cambridge, MA 02139, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/21979

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