痢疾杆菌是人类细菌性痢疾的主要病原菌，其通过三型分泌系统将毒性效应蛋白分子注射到宿主细胞中,效应蛋白作用于宿主关键信号分子,从而调节宿主信号通路,以利于细菌的入侵与感染，因此效应蛋白是痢疾杆菌的关键致病因子，在与宿主相互作用过程中发挥最重要的作用。我们综合运用微生物、生化、细胞、结构等研究手段，通过鉴定效应蛋白的生化活性和宿主靶分子，阐明效应蛋白调节宿主信号通路的致病分子机制。申请人先前已成功揭示4个痢疾杆菌效应蛋白的全新分子机理，实验室先后在Cell、PLOS Pathogens等上发表相关研究论文，并获得其他良好的前期进展。在此前工作基础上，本项研究计划以机制未知的痢疾杆菌重要效应蛋白IcsB、OspC1和OspB为研究对象，探索它们调节宿主信号通路的分子机理；同时以具有全新泛素连接酶活性的效应蛋白IpaH3为研究对象，研究效应蛋白与宿主分子的新型相互作用机制，尝试将效应蛋白应用成真核细胞生物学研究的新工具。

Shigella，the causative agent of human Shigellosis, delivers many virulent effector proteins into the host cells via its special type III secretion system. The injected effectors target the host key signaling molecules to manipulate the host signaling pathways for bacterial infection and proliferation. Therefore, the type III effectors are the weapons of Shigella and play key roles in its infection process. We utilize multiple-disciplinary approaches of microbiology, biochemistry, cell biology and structural biology to identify the biochemical activities and host targets of Shigella effectors to uncover their molecular mechanisms in modulating the host signaling. We have uncovered the novel mechanisms of four Shigella effectors and published two papers as corresponding author in Cell and PLOS Pathogens, respectively. In this study, we plan to study the molecular mechanisms of three important Shigella effectors: IcsB, OspC1 and OspB. We will also investigate the novel interaction mechanism of IpaH3, a Shigella effector with the new-type ubiquitin E3 ligase activity, with its host E2 enzyme UbcH5, and try to apply IpaH3 as a new research tool in eukaryotic cell signaling studies.