mTORC1通路作为细胞代谢的重要枢纽，在肿瘤、衰老及糖尿病等疾病中发挥着重要作用，其活性主要受溶酶体上两类关键小G蛋白Rags和Rheb的调控。以往对mTORC1通路的研究主要集中在Rags和Rheb的活性调控上，而Rags与Rheb协同调控mTORC1的机制尚未阐明。近期申请人发现细胞内Rheb能与RagC结合，而自噬接头蛋白SQSTM1在这个过程中发挥着重要的作用。更重要的是，SQSTM1的剪切体SQSTM1b能够更强的促进Rheb与RagC结合。同时，申请人还发现Rheb泛素化修饰在结肠癌发生发展过程中发挥重要的作用。基于此，我们提出泛素化修饰与SQSTM1b协同介导Rheb与Rags的结合是mTORC1活化的重要机制。本项目将进一步研究Rheb的泛素化修饰在该过程中的作用，揭示mTORC1的调控机制，阐述泛素化修饰与SQSTM1b的协同作用在细胞增殖及肿瘤发生发展过程中的重要性。

Mechanistic target of rapamycin complex 1 (mTORC1) is an essential signaling pathway that integrates several environmental stimuli to regulate tumor, aging and diabetes, its activation is mainly regulated by lysosomal small G protein Rags and Rheb. Previous studies were mainly focus on the regulatory effect on the activation of Rags and Rheb. However, the mechanism of Rags and Rheb synergistic regulates mTORC1 was still unclear. Our preliminary results suggest that SQSTM1 was a crucial scaffold protein that can promote the interaction between Rags and Rheb. There are two variants of SQSTM1 in cells, SQSTM1a and SQSTM1b. SQSTM1b showed stronger promotion effect on the interation between RagC and Rheb than SQSTM1a. More interestingly, we found that Rheb is modified by ubiquitination, which plays a dominant role in the progress of colon cancer. Based on these results, we proposed that ubiquitination and SQSTM1 may synergistically regulate the interaction of RagC and Rheb and result in the activation of mTORC1. In the future, we will figure out the underlying mechanism of the ubiquitination regulating the interaction between RagC and Rheb, and investigate the role of ubiquitination and SQSTM1b in mTORC1 activation, cell proliferation and tumorigenesis.