mTORC1通路在细胞代谢和肿瘤发生发展中起重要作用。Ragulator作为小G蛋白Rags活性调控的重要因子，与Rags的结合是mTORC1定位到溶酶体上并激活的核心。但外界信号调控Ragulator-Rags这一复合体的形成的机制一直不清楚。申请人前期发现Ragulator的重要组成蛋白p18能发生泛素化修饰，并且其泛素化修饰受到氨基酸信号的调控。更重要的是，申请人发现p18的泛素化修饰能够促进Ragulator与Rags的结合及mTORC1活性。基于此，申请人提出Ragulator的泛素化修饰是介导其与Rags结合并激活mTORC1的重要机制。本项目将进一步研究Ragulator的泛素化修饰，揭示氨基酸激活mTORC1的调控机制，筛选靶向去泛素化酶的小分子化合物，阐述Ragulator的泛素化修饰对细胞代谢及肿瘤发生发展的作用，以期为临床上代谢相关疾病的分子诊断及防治提供理论依据。

mTORC1 pathway is a master regulator of cell metabolism and tumorigenesis. Ragulator is the GEF（guanine nucleotide exchange factor）of Rags, and is indispensable for Rags mediated lysosomal localization of mTORC1. However, the mechanism of interaction between Ragulator and Rags was still unclear. Our preliminary results found that p18, a key component of Regulator, can be ubiquitinated, and the ubiquitination could be regulated by amino acid. More importantly, the ubiquitination affected the interaction between p18 and Rags. Based on these results, we proposed that ubiquitination of p18 is important for the interaction between Ragulator and Rags and the activation of mTORC1. In the future, we plan to take further research in investigating the mechanism of how the ubiquitination of Ragulator regulates mTORC1 activation, screening small molecule compound that targets ubiquitin enzymes, expositing the effect of ubiquitination on cell metabolism and tumorigenesis. Our study will provide theoretical foundation for the diagnose, prophylaxis and treatment of metabolic disease.