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      Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A

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          Summary

          The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and metabolism. Leucine (Leu) activates mTORC1 and many have tried to identify the mechanisms whereby cells sense Leu in this context. Here we describe that the Leu metabolite acetyl-coenzyme A (AcCoA) positively regulates mTORC1 activity by EP300-mediated acetylation of the mTORC1 regulator, Raptor, at K1097. Leu metabolism and consequent mTORC1 activity are regulated by intermediary enzymes. As AcCoA is a Leu metabolite, this process directly correlates with Leu abundance, and does not require Leu sensing via intermediary proteins, as has been described previously. Importantly, we describe that this pathway regulates mTORC1 in a cell-type-specific manner. Finally, we observed decreased acetylated Raptor, and inhibited mTORC1 and EP300 activity in fasted mice tissues. These results provide a direct mechanism for mTORC1 regulation by Leu metabolism.

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          Highlights

          • Leucine metabolizing enzymes impact mTORC1 activity

          • AcCoA, the final leucine metabolite, regulates mTORC1 activity by Raptor acetylation

          • AcCoA regulates mTORC1 in a cell-type-specific manner

          • Fasted tissues in mice have decreased AcCoA, acetylated Raptor, and mTORC1 activity

          Abstract

          Son et al. find that the leucine metabolite, acetyl-coenzyme A, promotes mTORC1 activity through EP300-mediated acetylation of Raptor, an mTORC1 regulator. The pathway that is cell-type specific, allows for intermediary enzymes to regulate mTORC1 activity, without a need for leucine sensing. In fasted mice, Raptor acetylation decreases in some tissues, leading to mTORC1 inhibition.

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          Most cited references13

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          Sestrin2 is a leucine sensor for the mTORC1 pathway.

          Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.
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            Amino acid signalling upstream of mTOR.

            Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H(+)-ATPase (v-ATPase).
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              Signal integration by mTORC1 coordinates nutrient input with biosynthetic output.

              Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, we discuss the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth. The emerging network of signalling pathways through which mTORC1 integrates systemic signals (secreted growth factors) with local signals (cellular nutrients - amino acids, glucose and oxygen - and energy, ATP) is detailed. Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology.
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                Author and article information

                Contributors
                Journal
                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                08 January 2019
                08 January 2019
                : 29
                : 1
                : 192-201.e7
                Affiliations
                [1 ]Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
                [2 ]UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK
                [3 ]Department of Anatomy, Bk21 Plus Project for Medical Sciences and Brain Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
                Author notes
                []Corresponding author dcr1000@ 123456cam.ac.uk
                [4]

                Lead Contact

                Article
                S1550-4131(18)30514-X
                10.1016/j.cmet.2018.08.013
                6331339
                30197302
                ff20685e-3113-4675-ace0-a79a59dc3bff
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 9 January 2018
                : 1 June 2018
                : 12 August 2018
                Categories
                Article

                Cell biology
                mtor,acetyl-coa,leucine,autophagy,starvation,amino acid sensing,raptor
                Cell biology
                mtor, acetyl-coa, leucine, autophagy, starvation, amino acid sensing, raptor

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