亮氨酸通过其代谢产物乙酰辅酶 A 向 mTORC1 发出信号。
Leucine Signals to mTORC1 via Its Metabolite Acetyl-Coenzyme A.
机构信息
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.
Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
出版信息
Cell Metab. 2019 Jan 8;29(1):192-201.e7. doi: 10.1016/j.cmet.2018.08.013. Epub 2018 Sep 6.
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.
雷帕霉素（mTOR）复合物 1（mTORC1）的机械靶点是细胞生长和代谢的主要调节剂。亮氨酸（Leu）激活 mTORC1，许多人试图确定细胞在这种情况下感知亮氨酸的机制。在这里，我们描述了亮氨酸代谢物乙酰辅酶 A（AcCoA）通过 EP300 介导的 mTORC1 调节剂 Raptor 在 K1097 处的乙酰化正向调节 mTORC1 活性。亮氨酸代谢和随之而来的 mTORC1 活性受中间酶调节。由于 AcCoA 是亮氨酸的代谢物，因此这个过程与亮氨酸的丰度直接相关，并不需要通过中间蛋白来感知亮氨酸，正如之前所描述的那样。重要的是，我们描述了这条途径以细胞类型特异性的方式调节 mTORC1。最后，我们观察到在禁食的小鼠组织中，乙酰化 Raptor 减少，mTORC1 和 EP300 活性受到抑制。这些结果为亮氨酸代谢对 mTORC1 的调节提供了一个直接的机制。
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