幽门螺杆菌CagA通过OTULIN调控LUBAC-NF-κB通路促炎癌转化的分子机制研究

幽门螺杆菌（HP）引起的慢性活动性胃炎是胃癌发生的最主要病因。CagA是HP感染的关键易感及驱动分子，但其促炎癌转化机制仍不清楚。课题组前期发现：CagA能促进NF-κB通路激活，且与LUBAC-NF-κB轴的关键分子OTULIN存在直接相互作用。因此我们提出“CagA与OTULIN互作抑制OTULIN对LUBAC的去泛素化修饰，促进LUBAC对NF-κB通路的激活”这一假设。本研究拟构建表达含有不同结构域的CagA和OTULIN截短蛋白，通过理化实验明确二者互作的结构域；并解析二者及其复合物的结构，阐明二者结合后对其空间构象的影响及互作的结构基础；最后从细胞和动物水平探明CagA对OTULIN去泛素化修饰的影响及调控LUBAC-NF-κB通路的机制。该研究将进一步阐明CagA促炎癌转化的分子机制，为基于CagA-OTULIN结构功能复合体的靶向药物设计奠定基础，以部分阻断炎癌转化。

Chronic active gastritis caused by Helicobacter pylori (HP) is the main cause of gastric cancer. CagA is a key susceptibility and driving molecule for HP infection, but its proinflammatory cancer transformation mechanism is still unclear. Our previous study showed that CagA can promote the activation of the NF-κB pathway, and can directly interact with the key molecule OTULIN of the LUBAC-NF-κB axis. Therefore, we propose the hypothesis that "CagA and OTULIN interact to inhibit the deubiquitination modification of LUBAC by OTULIN and promote the activation of NF-κB pathway by LUBAC." In present study, we plan to construct CagA and OTULIN truncated proteins that contain different domains. Through physicochemical experiments, we can identify the domains where the two interact with each other, and analyze the structure of the two and their complexes, clarify the influence of the two on their spatial conformation and the structural basis of interaction; finally, the effects of CagA on the deubiquitination modification of OTULIN and the mechanism of regulating the LUBAC-NF-κB pathway are explored from the cellular and animal levels. This study will further clarify the molecular mechanism of CagA promoting inflammatory cancer transformation, and lay the foundation for the design of targeted drugs based on CagA-OTULIN structure-function complex to partially block inflammatory cancer transformation.