Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A.
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Authors
Son, Sung Min
Park, So Jung
Lee, Huikyong
Lee, Jong Eun
Menzies, Fiona M
Rubinsztein, David C
Publication Date
2019-01-08Journal Title
Cell Metab
ISSN
1550-4131
Publisher
Elsevier BV
Volume
29
Issue
1
Pages
192-201.e7
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Son, S. M., Park, S. J., Lee, H., Siddiqi, F., Lee, J. E., Menzies, F. M., & Rubinsztein, D. C. (2019). Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A.. Cell Metab, 29 (1), 192-201.e7. https://doi.org/10.1016/j.cmet.2018.08.013
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.
Keywords
Raptor, acetyl-CoA, amino acid sensing, autophagy, leucine, mTOR, starvation, Acetyl Coenzyme A, Animals, Cell Line, E1A-Associated p300 Protein, Female, Humans, Leucine, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Regulatory-Associated Protein of mTOR
Sponsorship
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (095317/Z/11/Z)
Identifiers
External DOI: https://doi.org/10.1016/j.cmet.2018.08.013
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280631
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