title: Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome.
abstract: Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function.
authors.affiliation: Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pharmacology University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ou
authors.affiliation: Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pharmacology University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Meilian
authors.initials: M
authors.lastname: Liu
authors.affiliation: Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
authors.affiliation: Metabolic Syndrome Research Center and Diabetes Center, Key Laboratory of Diabetes Immunology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pharmacology University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007930:Leucine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020304:Raptors / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000097245:Ursolic Acid
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D051057:Proto-Oncogene Proteins c-akt; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000097245:Ursolic Acid; C490213:Rheb protein, mouse; C000624651:Tsc1 protein, mouse; C570841:deptor protein, mouse; C546843:mTOR protein, mouse; C000589376:Rragb protein, Mouse
references.citation: Am J Physiol Endocrinol Metab. 2001 Sep;281(3):E466-71
references.pmid: 11500301
references.citation: Curr Drug Targets. 2011 Jul 1;12(8):1223-31
references.pmid: 21561413
references.citation: Cell Res. 2007 Aug;17(8):666-81
references.pmid: 17680028
references.citation: J Clin Endocrinol Metab. 2002 Dec;87(12):5553-8
references.pmid: 12466352
references.citation: Science. 2008 Jun 13;320(5882):1496-501
references.pmid: 18497260
references.citation: Mol Cell Biol. 2008 Jun;28(12):4104-15
references.pmid: 18411301
references.citation: PLoS One. 2012;7(3):e32476
references.pmid: 22427843
references.citation: J Hepatol. 2011 Aug;55(2):379-87
references.pmid: 21168456
references.citation: J Clin Invest. 2011 Nov;121(11):4477-90
references.pmid: 21965330
references.citation: Cell. 2013 May 9;153(4):840-54
references.pmid: 23663782
references.citation: Dev Cell. 2011 Jan 18;20(1):97-108
references.pmid: 21238928
references.citation: Science. 2013 May 31;340(6136):1100-6
references.pmid: 23723238
references.citation: Curr Med Chem. 2013;20(7):908-31
references.pmid: 23210780
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Trends Endocrinol Metab. 2011 Mar;22(3):94-102
references.pmid: 21269838
references.citation: J Nat Prod. 2011 Jul 22;74(7):1640-4
references.pmid: 21648406
references.citation: Biochem Soc Trans. 2013 Aug;41(4):906-12
references.pmid: 23863154
references.citation: Mol Cell. 2010 Oct 22;40(2):310-22
references.pmid: 20965424
references.citation: Dev Cell. 2006 Dec;11(6):859-71
references.pmid: 17141160
references.citation: Br J Pharmacol. 2012 Mar;165(6):1813-1826
references.pmid: 21950524
references.citation: Nature. 1977 Dec 22-29;270(5639):725-7
references.pmid: 563524
references.citation: Science. 2011 Nov 4;334(6056):678-83
references.pmid: 22053050
references.citation: J Biol Chem. 2010 Nov 19;285(47):36387-94
references.pmid: 20851890
references.citation: J Biol Chem. 1999 Apr 23;274(17):11647-52
references.pmid: 10206976
references.citation: Nat Cell Biol. 2002 Sep;4(9):699-704
references.pmid: 12172555
references.citation: Int J Cancer. 2013 Dec 15;133(12):2781-90
references.pmid: 23737395
references.citation: Cell. 2002 Jul 26;110(2):177-89
references.pmid: 12150926
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14238-43
references.pmid: 16176982
references.citation: Cell. 2002 Jul 26;110(2):163-75
references.pmid: 12150925
references.citation: Cell Metab. 2010 May 5;11(5):390-401
references.pmid: 20444419
references.citation: Cell. 2010 Apr 16;141(2):290-303
references.pmid: 20381137
references.citation: Science. 2013 Mar 15;339(6125):1323-8
references.pmid: 23429703
references.citation: Mol Nutr Food Res. 2010 Nov;54(11):1609-17
references.pmid: 20521271
references.citation: Cell. 2011 Aug 5;146(3):408-20
references.pmid: 21816276
references.citation: Cell. 2009 May 29;137(5):873-86
references.pmid: 19446321
references.citation: Diabetes. 1988 Jun;37(6):667-87
references.pmid: 3289989
references.citation: Biochem J. 2008 Jun 1;412(2):179-90
references.pmid: 18466115
references.citation: Chem Biol Interact. 2010 Dec 5;188(3):635-42
references.pmid: 20869956
references.citation: Mol Nutr Food Res. 2010 Sep;54(9):1285-95
references.pmid: 20352621
references.citation: PLoS One. 2012;7(6):e39332
references.pmid: 22745735
references.citation: J Biol Chem. 2011 Jan 7;286(1):60-6
references.pmid: 20980258
references.citation: Amino Acids. 2010 May;38(5):1533-9
references.pmid: 19882215
references.citation: Cell. 2012 Sep 14;150(6):1196-208
references.pmid: 22980980
references.citation: Neurosci Lett. 2009 Nov 13;465(2):177-80
references.pmid: 19682542
references.citation: Cell. 2006 Feb 10;124(3):471-84
references.pmid: 16469695
references.citation: Endocrinology. 2005 Mar;146(3):1473-81
references.pmid: 15604215