O-糖基化修饰调控mTORC1信号通路的机制和功能研究

mTORC1信号通路作为细胞感应微环境的重要枢纽，是细胞代谢和增殖平衡的重要保障，其功能异常与肿瘤的发生发展密切相关。O-糖基化修饰（O-GlcNAcylation）是由葡萄糖代谢中间产物尿苷二磷酸乙酰葡糖胺（UDP-GlcNAc）介导的一种重要的蛋白质翻译后修饰。但葡萄糖介导的O-糖基化修饰是否参与mTORC1信号通路调控并不清楚。申请人发现，葡萄糖能够促进mTORC1信号通路的重要调控蛋白RagD在Gtr结构域发生O-糖基化修饰，且该修饰受经典的O-糖基化修饰调控蛋白OGT和OGA的调控，同时OGT在结直肠癌中呈现高表达。基于此，申请人提出葡萄糖介导RagD的O-糖基化修饰是激活mTORC1的重要机制。本项目将进一步揭示RagD O-糖基化修饰调控mTORC1的机制及功能，阐述RagD O-糖基化修饰对结直肠癌发生发展的作用，以期为结直肠癌等肿瘤的分子诊断及治疗提供理论依据。

The mTORC1 signaling pathway, as an important hub for cells to sense the microenvironment, is an important guarantee for the balance of cell metabolism and proliferation, and its abnormal function is closely related to the occurrence and development of tumors. O-GlcNAcylation is an important post-translational modification of protein mediated by uridine diphosphate acetylglucosamine (UDP-GlcNAc), an intermediate product of glucose metabolism. However, it is not clear whether glucose-mediated O-GlcNAcylation is involved in the regulation of mTORC1 signaling pathway. The applicant found that glucose can promote the O-GlcNAcylation modification in the Gtr domain of the important regulatory protein RagD of the mTORC1 signaling pathway, and this modification is regulated by the classical O-GlcNAcylation modification regulatory proteins OGT and OGA, while OGT is highly expressed in colorectal cancer. Based on this, the applicant proposes that glucose-mediated O-GlcNAcylation of RagD is an important mechanism for activating mTORC1. This project will further reveal the mechanism and function of RagD O-GlcNAcylation to regulate mTORC1, and explain the role of RagD O-GlcNAcylation on the occurrence and development of colorectal cancer, in order to provide a theory for the molecular diagnosis and treatment of colorectal cancer and other tumors.