胞浆甘氨酰-tRNA合成酶cytoGARS感知甘氨酸的分子机制及其对肝细胞癌的影响

感知分子识别特定氨基酸，传递信号并激活mTORC1通路，对氨基酸代谢调控至关重要。甘氨酸（Gly）代谢异常与肝细胞癌（HCC）密切相关，然而Gly感知机制及其对HCC的影响尚不清楚。课题组前期利用HCC细胞对Gly结合蛋白进行筛选，发现下调甘氨酰-tRNA合成酶（GARS）抑制Gly激活mTORC1。并且GARS在HCC中高表达，其胞浆形式（cytoGARS）促进mTORC1和细胞生长。因此我们假设：cytoGARS可能不依赖其氨酰酶活性，感知Gly，激活mTORC1，促进HCC发生。该项目利用经典肿瘤生物学、最新转录组学和蛋白组学技术，在分子、细胞和动物水平，结合临床样本，探讨1）cytoGARS感知Gly的模式及激活mTORC1的机制；2）cytoGARS感知Gly对HCC的影响及下游效应通路。该项目将揭示cytoGARS感知Gly的新功能和机制，阐明HCC发病机理，为其提供治疗靶标。

Amino acid sensing is a crucial step in the regulation of amino acid metabolism. The sensor recognizes the specific amino acid, transmits the signal to, and activates the mTORC1 signaling. Abnormal glycine (Gly) metabolism is closely related to the occurrence of hepatocellular carcinoma (HCC). However, the underlying mechanisms and functions of Gly-sensing in HCC progression remain elusive. Through screening the Gly-binding proteins in HCC cells, our previous studies found that knockdown of Glycyl-tRNA synthetase (GARS) inhibits Gly-induced mTORC1 activation. Furthermore, we found that GARS is highly expressed in HCC, and the cytosolic form of GARS (cytoGARS) promotes the mTORC1 signaling and HCC cell growth. These results suggest that cytoGARS may serve as a Gly-sensor, activating the mTORC1 signaling and promoting HCC progression, independent of its tRNA-aminoacylation activity. To prove the hypothesis, we investigate the following: 1) the Gly-sensing mode of cytoGARS and the underlying mechanism of mTORC1 activation; 2) the Gly-sensing role of cytoGARS in HCC progression and the downstream effector pathway. We test the hypothesis in cellular and animal models as well as clinical HCC samples by using a series of classic cancer-biology techniques, in combination with the latest transcriptomic and proteomic techniques. This project will not only identify the novel mechanism and function of cytoGARS in Gly-sensing but also elucidate the mechanism of HCC development, providing the potential therapeutic target.