Helicobacter pylori cag-Type IV Secretion System: Integrin interaction and mechanism of CagA protein translocation

幽门螺杆菌是一种革兰氏阴性细菌，约占人类总数的50%，在胃粘膜中定植。幽门螺杆菌感染与许多胃十二指肠疾病有关，包括慢性胃炎、消化性溃疡、腺癌和粘膜相关淋巴组织(MALT)淋巴瘤。某些Hp菌株携带CAG致病岛(CAG-PAI)，该岛编码IV型分泌系统(T4SS)，将细菌癌蛋白CagA运送到胃上皮细胞的细胞质中。CAG-T4SS由约30个蛋白质组成，形成细菌跨膜通道和表面相关的针状毛结构(注射体)。我们最近在T4SS菌毛顶端发现了CagA(易位效应蛋白)和Cagy，并发现CagA、CagI和Cagy与宿主细胞表面的β-1整合素受体相互作用。在本项目中，我们有兴趣了解(1)T4SS菌毛形成的信号过程和诱导机制，(2)不同CAG蛋白与整合素受体的精确相互作用，以及(3)Hp CAG-T4SS转位CagA蛋白的基本机制。我们希望揭开细菌T4SS中蛋白质转位的全新机制，这一结果可能对许多其他细菌病原体具有重要意义。

Helicobacter pylori is a Gram-negative bacterial pathogen, colonizing the gastric mucosa of about 50% of the human population. H. pylori infection is associated with a number of gastroduodenal diseases, including chronic gastritis, peptic ulcers, adenocarcinoma and mucosa-associated-lymphoid tissue (MALT) lymphoma. Certain H. pylori strains carry the cag-pathogenicity island (cag-PAI), which encodes a Type IV Secretion System (T4SS) to deliver the bacterial oncoprotein CagA into the cytoplasm of gastric epithelial cells. The cag- T4SS consists of about 30 proteins, forming a bacterial transmembrane channel and a surface-associated needle-like pilus structure (injectisome). We recently identified CagA (the translocated effector protein) and CagY on the tip of the T4SS pilus, and CagA, CagI and CagY were found to interact with β1 integrin receptors on the host cell surface. In this project we are interested to understand (1) the signaling process and the mechanism for induction of T4SS pilus formation, (2) the precise interaction of the different Cag proteins with the integrin receptor, and (3) the basic mechanism of CagA protein translocation by the H. pylori cag- T4SS. We expect to unravel a completely novel mechanism of protein translocation in a bacterial T4SS and the results might be of importance for many other bacterial pathogens.