Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway
Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway
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DOI：
10.1016/j.cell.2012.02.044
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发表时间：
2012-04-13
期刊：
影响因子：
64.5
通讯作者：
Kim, Sunghoon
中科院分区：
文献类型：
--
作者：
Han, Jung Min;Jeong, Seung Jae;Kim, Sunghoon
氨基酸是激活哺乳动物雷帕霉素靶蛋白（mTOR）激酶所必需的，该激酶调节蛋白质翻译、细胞大小和自噬。然而，直接将细胞内氨基酸介导的信号传导与mTORC 1偶联的氨基酸传感器尚不清楚。在这里，我们表明，亮氨酰-tRNA合成酶（LRS）在氨基酸诱导的mTORC 1激活中起着关键作用，通过传感细胞内亮氨酸浓度和启动分子事件导致mTORC 1激活。对于亮氨酸结合重要的LRS氨基酸残基的突变使得mTORC 1途径对细胞内氨基酸水平不敏感。我们表明，LRS直接结合到Rag GTdR，氨基酸信号转导mTORC 1的介质，在一个氨基酸依赖性的方式和功能作为一个GTP酶激活蛋白（GAP）的Rag GTdR激活mTORC 1。这项工作表明，LRS是氨基酸信号传导到mTORC 1的关键介质。
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.