Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A

Sung Min Son; So Jung Park; Huikyong Lee; Farah Siddiqi; Jong Eun Lee; Fiona M. Menzies; David C. Rubinsztein

doi:10.1016/j.cmet.2018.08.013

Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A

Sung Min Son, So Jung Park, Huikyong Lee, Farah Siddiqi, Jong Eun Lee, Fiona M. Menzies, David C. Rubinsztein

Department of Anatomy

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	192-201.e7
Journal	Cell Metabolism
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2018.08.013
Publication status	Published - 2019 Jan 8

Bibliographical note

Funding Information:
We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK, and the Alzheimer's Society), Wellcome Trust (Principal Research Fellowship to D.C.R. [095317/Z/11/Z]), Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), Roger de Spoelberch Foundation, Alzheimer's Research UK, Addenbrooke's Charitable Trust, National Institute for Health Research Cambridge Biomedical Research Centre (to D.C.R.), and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2173 to S.M.S. and J.E.L.; HI14C1913 to H.L. and S.J.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Funding Information:
We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK, and the Alzheimer's Society), Wellcome Trust (Principal Research Fellowship to D.C.R. [ 095317/Z/11/Z ]), Strategic Grant to Cambridge Institute for Medical Research ( 100140/Z/12/Z ), Roger de Spoelberch Foundation , Alzheimer’s Research UK , Addenbrooke’s Charitable Trust , National Institute for Health Research Cambridge Biomedical Research Centre (to D.C.R.), and the Korean Health Technology R&D Project , Ministry of Health & Welfare, Republic of Korea ( HI14C2173 to S.M.S. and J.E.L.; HI14C1913 to H.L. and S.J.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Publisher Copyright:
© 2018 The Authors

All Science Journal Classification (ASJC) codes

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2018.08.013

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title = "Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A",

abstract = "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.",

author = "Son, {Sung Min} and Park, {So Jung} and Huikyong Lee and Farah Siddiqi and Lee, {Jong Eun} and Menzies, {Fiona M.} and Rubinsztein, {David C.}",

note = "Funding Information: We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK, and the Alzheimer's Society), Wellcome Trust (Principal Research Fellowship to D.C.R. [095317/Z/11/Z]), Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), Roger de Spoelberch Foundation, Alzheimer's Research UK, Addenbrooke's Charitable Trust, National Institute for Health Research Cambridge Biomedical Research Centre (to D.C.R.), and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2173 to S.M.S. and J.E.L.; HI14C1913 to H.L. and S.J.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK, and the Alzheimer's Society), Wellcome Trust (Principal Research Fellowship to D.C.R. [ 095317/Z/11/Z ]), Strategic Grant to Cambridge Institute for Medical Research ( 100140/Z/12/Z ), Roger de Spoelberch Foundation , Alzheimer{\textquoteright}s Research UK , Addenbrooke{\textquoteright}s Charitable Trust , National Institute for Health Research Cambridge Biomedical Research Centre (to D.C.R.), and the Korean Health Technology R&D Project , Ministry of Health & Welfare, Republic of Korea ( HI14C2173 to S.M.S. and J.E.L.; HI14C1913 to H.L. and S.J.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2018 The Authors",

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AU - Siddiqi, Farah

AU - Lee, Jong Eun

AU - Menzies, Fiona M.

AU - Rubinsztein, David C.

N1 - Funding Information: We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK, and the Alzheimer's Society), Wellcome Trust (Principal Research Fellowship to D.C.R. [095317/Z/11/Z]), Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), Roger de Spoelberch Foundation, Alzheimer's Research UK, Addenbrooke's Charitable Trust, National Institute for Health Research Cambridge Biomedical Research Centre (to D.C.R.), and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2173 to S.M.S. and J.E.L.; HI14C1913 to H.L. and S.J.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Funding Information: We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK, and the Alzheimer's Society), Wellcome Trust (Principal Research Fellowship to D.C.R. [ 095317/Z/11/Z ]), Strategic Grant to Cambridge Institute for Medical Research ( 100140/Z/12/Z ), Roger de Spoelberch Foundation , Alzheimer’s Research UK , Addenbrooke’s Charitable Trust , National Institute for Health Research Cambridge Biomedical Research Centre (to D.C.R.), and the Korean Health Technology R&D Project , Ministry of Health & Welfare, Republic of Korea ( HI14C2173 to S.M.S. and J.E.L.; HI14C1913 to H.L. and S.J.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Publisher Copyright: © 2018 The Authors

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N2 - 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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Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A

Abstract

Bibliographical note

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