Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome.
Ursolic acid inhibits leucine-stimulated mTORC1 signaling by suppressing mTOR localization to lysosome.
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熊果酸通过抑制 mTOR 定位至溶酶体来抑制亮氨酸刺激的 mTORC1 信号传导
DOI：
10.1371/journal.pone.0095393
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Ou X;Liu M;Luo H;Dong LQ;Liu F
熊果酸(UA)是一种广泛存在于中草药和水果中的五环三萜类化合物，具有降血糖、减肥、抗癌等多种功效。然而，UA作用的分子机制在很大程度上仍不清楚。在这里，我们发现UA抑制亮氨酸诱导的C2C12肌管中雷帕霉素复合体机械靶1(MTORC1)信号通路的激活。UA介导的对mTORC1的抑制不依赖于Akt、结节性硬化症复合体1/2(TSC1/2)和脑内富含RAS的同系物(Rheb)，这表明UA通过靶向这些mTOR调节器下游的位置负向调节mTORC1信号转导。UA处理不影响mTOR与其激活剂Raptor或抑制剂Deptor的相互作用，但抑制RagB与Raptor的结合，并抑制亮氨酸诱导的mTOR溶酶体定位。综上所述，我们的研究确定UA是mTORC1信号通路的直接负调控因子，并提出了UA发挥其有益功能的新机制。
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.
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