Yuan Wenjie, Guo Shuguang, Gao Jiaoqi, Zhong Mingming, Yan Gonghong, Wu Wangmeng, Chao Yapeng, Jiang Yu
From the School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and.
J Biol Chem. 2017 Feb 17;292(7):2660-2669. doi: 10.1074/jbc.M116.772194. Epub 2017 Jan 5.
In eukaryotic cells, two conserved protein kinases, Gcn2 and TOR complex 1 (TORC1), couple amino acid conditions to protein translation. Gcn2 functions as an amino acid sensor and is activated by uncharged tRNAs that accumulate when intracellular amino acids are limited. Activated Gcn2 phosphorylates and inhibits eukaryotic initiation factor-2α (eIF2α), resulting in repression of general protein synthesis. Like Gcn2, TORC1 is also involved in sensing amino acid conditions. However, the underlying mechanism remains unclear. In the present study, we show that TORC1 is a direct target of Gcn2 kinase in the yeast In response to amino acid starvation, Gcn2 binds to TORC1 and phosphorylates Kog1, the unique regulatory subunit of TORC1, resulting in down-regulation of TORC1 kinase activity. In the absence of Gcn2, TORC1 signaling activity increases and becomes unresponsive to amino acid starvation. Our findings demonstrate that TORC1 is an effector of Gcn2 in amino acid signaling, hence defining a novel mechanism by which TORC1 senses amino acid starvation.
在真核细胞中，两种保守的蛋白激酶，即Gcn2和雷帕霉素靶蛋白复合物1（TORC1），将氨基酸状况与蛋白质翻译联系起来。Gcn2作为一种氨基酸传感器，被细胞内氨基酸有限时积累的空载tRNA激活。激活的Gcn2磷酸化并抑制真核起始因子-2α（eIF2α），导致一般蛋白质合成受到抑制。与Gcn2一样，TORC1也参与感知氨基酸状况。然而，其潜在机制仍不清楚。在本研究中，我们表明在酵母中TORC1是Gcn2激酶的直接靶点。响应氨基酸饥饿时，Gcn2与TORC1结合并磷酸化TORC1的独特调节亚基Kog1，导致TORC1激酶活性下调。在没有Gcn2的情况下，TORC1信号活性增加，并且对氨基酸饥饿不再有反应。我们的研究结果表明，TORC1是Gcn2在氨基酸信号传导中的效应器，从而定义了一种TORC1感知氨基酸饥饿的新机制。
