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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 references 26

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          mTOR signaling in growth control and disease.

          The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.
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            mTOR: from growth signal integration to cancer, diabetes and ageing.

            In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.
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              mTOR Signaling in Growth, Metabolism, and Disease.

              The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.
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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
                © 2018 The Authors

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

                Categories
                Article

                Cell biology

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

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