Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome

• Published in: PloS one Vol. 9; no. 4; p. e95393
• Main Authors: Ou, Xiang, Liu, Meilian, Luo, Hairong, Dong, Lily Q, Liu, Feng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.04.2014; Public Library of Science (PLoS)
• Subjects: Acids; AKT protein; Animals; Biology and Life Sciences; Brain; Cancer; Cell Differentiation; Cell Line; Gene Expression Regulation; Glucose; Herbal medicine; Homology; Hyperglycemia; Inhibition; Insulin resistance; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Leucine; Leucine - antagonists & inhibitors; Leucine - pharmacology; Localization; Lysosomes - drug effects; Lysosomes - metabolism; Mechanistic Target of Rapamycin Complex 1; Medicinal herbs; Mice; Molecular modelling; Monomeric GTP-Binding Proteins - genetics; Monomeric GTP-Binding Proteins - metabolism; Multiprotein Complexes - agonists; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Myotubes; Neuropeptides - genetics; Neuropeptides - metabolism; Plasmids; Protein Binding; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Raptors - genetics; Raptors - metabolism; Ras Homolog Enriched in Brain Protein; Regulators; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Triterpenes - pharmacology; Tuberous sclerosis; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ursolic Acid; United States > US; Texas; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0095393

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.