Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway
Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway
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DOI：
10.1073/pnas.1801287115
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发表时间：
2018-06-05
影响因子：
11.1
通讯作者：
Han, Jung Min
中科院分区：
文献类型：
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作者：
Lee, Minji;Kim, Jong Hyun;Han, Jung Min
一种蛋白质合成酶，亮氨酸- trna合成酶（LRS），作为雷帕霉素复合物1 （mTORC1）机制靶点的亮氨酸传感器，是蛋白质合成、代谢、自噬和细胞生长的中心效应物。然而，其在mTORC1信号传导和肿瘤生长中的意义以及与其他亮氨酸信号介质的功能关系尚不清楚。在这里，我们展示了在赖氨酸信号传导过程中Rag GTPase循环的动力学，并且LRS通过GTP水解RagD作为启动“ON”开关，驱动整个Rag GTPase循环，而Sestrin2通过控制Rag GTPase- mtorc1轴上RagB的GTP水解而作为“OFF”开关。在肿瘤组织和细胞中，LRS-RagD轴与mTORC1活性呈正相关。RagD-RagB对的GTP-GDP循环，而不是RagC-RagA对，对亮氨酸诱导的mTORC1激活至关重要。活跃的RagD-RagB对可以克服RagC-RagA对的缺失，但反之则不然。这项工作表明，由LRS和Sestrin2协调的RagD-RagB的GTPase周期对控制mTORC1激活至关重要，因此将扩展目前对氨基酸敏感机制的理解。
A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating "ON" switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an "OFF" switch by controlling GTP hydrolysis of RagB in the Rag GTPase-mTORC1 axis. The LRS-RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP-GDP cycle of the RagD-RagB pair, rather than the RagC-RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD-RagB pair can overcome the absence of the RagC-RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD-RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acidsensing mechanism.