PMID- 30197302
OWN - NLM
STAT- MEDLINE
DCOM- 20200224
LR  - 20220129
IS  - 1932-7420 (Electronic)
IS  - 1550-4131 (Print)
IS  - 1550-4131 (Linking)
VI  - 29
IP  - 1
DP  - 2019 Jan 8
TI  - Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A.
PG  - 192-201.e7
LID - S1550-4131(18)30514-X [pii]
LID - 10.1016/j.cmet.2018.08.013 [doi]
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.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Son, Sung Min
AU  - Son SM
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), 
      University of Cambridge, Cambridge, UK; UK Dementia Research Institute, Cambridge 
      Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
FAU - Park, So Jung
AU  - Park SJ
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), 
      University of Cambridge, Cambridge, UK.
FAU - Lee, Huikyong
AU  - Lee H
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), 
      University of Cambridge, Cambridge, UK.
FAU - Siddiqi, Farah
AU  - Siddiqi F
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), 
      University of Cambridge, Cambridge, UK.
FAU - Lee, Jong Eun
AU  - Lee JE
AD  - Department of Anatomy, Bk21 Plus Project for Medical Sciences and Brain Research 
      Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
FAU - Menzies, Fiona M
AU  - Menzies FM
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), 
      University of Cambridge, Cambridge, UK.
FAU - Rubinsztein, David C
AU  - Rubinsztein DC
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), 
      University of Cambridge, Cambridge, UK; UK Dementia Research Institute, Cambridge 
      Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK. 
      Electronic address: dcr1000@cam.ac.uk.
LA  - eng
GR  - Wellcome Trust/United Kingdom
GR  - UKDRI-2002/MRC_/Medical Research Council/United Kingdom
GR  - 095317/Z/11/Z/WT_/Wellcome Trust/United Kingdom
GR  - 100140/Z/12/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180906
PL  - United States
TA  - Cell Metab
JT  - Cell metabolism
JID - 101233170
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 72-89-9 (Acetyl Coenzyme A)
RN  - EC 2.3.1.48 (E1A-Associated p300 Protein)
RN  - EC 2.3.1.48 (EP300 protein, human)
RN  - EC 2.3.1.48 (Ep300 protein, mouse)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Acetyl Coenzyme A/*metabolism
MH  - Animals
MH  - Cell Line
MH  - E1A-Associated p300 Protein/*metabolism
MH  - Female
MH  - Humans
MH  - Leucine/*physiology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Regulatory-Associated Protein of mTOR/*metabolism
PMC - PMC6331339
OTO - NOTNLM
OT  - Raptor
OT  - acetyl-CoA
OT  - amino acid sensing
OT  - autophagy
OT  - leucine
OT  - mTOR
OT  - starvation
EDAT- 2018/09/11 06:00
MHDA- 2020/02/25 06:00
PMCR- 2019/01/08
CRDT- 2018/09/11 06:00
PHST- 2018/01/09 00:00 [received]
PHST- 2018/06/01 00:00 [revised]
PHST- 2018/08/12 00:00 [accepted]
PHST- 2018/09/11 06:00 [pubmed]
PHST- 2020/02/25 06:00 [medline]
PHST- 2018/09/11 06:00 [entrez]
PHST- 2019/01/08 00:00 [pmc-release]
AID - S1550-4131(18)30514-X [pii]
AID - 10.1016/j.cmet.2018.08.013 [doi]
PST - ppublish
SO  - Cell Metab. 2019 Jan 8;29(1):192-201.e7. doi: 10.1016/j.cmet.2018.08.013. Epub 
      2018 Sep 6.