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 | |
| Publication status | Published - 2019 Jan 8 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Molecular Biology
- Cell Biology
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Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A. / Son, Sung Min; Park, So Jung; Lee, Huikyong; Siddiqi, Farah; Lee, Jong Eun; Menzies, Fiona M.; Rubinsztein, David C.
In: Cell Metabolism, Vol. 29, No. 1, 08.01.2019, p. 192-201.e7.Research output: Contribution to journal › Article
TY - JOUR
T1 - Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A
AU - Son, Sung Min
AU - Park, So Jung
AU - Lee, Huikyong
AU - Siddiqi, Farah
AU - Lee, Jong Eun
AU - Menzies, Fiona M.
AU - Rubinsztein, David C.
PY - 2019/1/8
Y1 - 2019/1/8
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058494304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058494304&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.08.013
DO - 10.1016/j.cmet.2018.08.013
M3 - Article
C2 - 30197302
AN - SCOPUS:85058494304
VL - 29
SP - 192-201.e7
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -