PDF(Pubmed)
Abstract：
Cell polarity is crucial for gastric mucosal barrier integrity and mainly regulated by polarity-regulating kinase partitioning-defective 1b (Par1b). During infection, the carcinogen Helicobacter pylori hijacks Par1b via the bacterial oncoprotein CagA leading to loss of cell polarity, but the precise molecular mechanism is not fully clear. Here we discovered a novel function of the actin-binding protein cortactin in regulating Par1b, which forms a complex with cortactin and the tight junction protein zona occludens-1 (ZO-1). We found that serine phosphorylation at S405/418 and the SH3 domain of cortactin are important for its interaction with both Par1b and ZO-1. Cortactin knockout cells displayed disturbed Par1b cellular localization and exhibited morphological abnormalities that largely compromised transepithelial electrical resistance, epithelial cell polarity, and apical microvilli. H. pylori infection promoted cortactin/Par1b/ZO-1 abnormal interactions in the tight junctions in a CagA-dependent manner. Infection of human gastric organoid-derived mucosoids supported these observations. We therefore hypothesize that CagA disrupts gastric epithelial cell polarity by hijacking cortactin, and thus Par1b and ZO-1, suggesting a new signaling pathway for the development of gastric cancer by Helicobacter.
摘要：
细胞极性对于胃粘膜屏障的完整性至关重要，主要受极性调节激酶分配缺陷1b（Par1b）的调节。在感染期间,致癌物幽门螺杆菌通过细菌癌蛋白CagA劫持Par1b，导致细胞极性丧失，但确切的分子机制尚不完全清楚。在这里，我们发现了肌动蛋白结合蛋白cortactin在调节Par1b中的新功能，与皮质肌动蛋白和紧密连接蛋白1（ZO-1）形成复合物。我们发现S405/418的丝氨酸磷酸化和皮质肌动蛋白的SH3结构域对于其与Par1b和ZO-1的相互作用是重要的。Cortactin敲除细胞显示Par1b细胞定位受到干扰，并表现出形态学异常，这在很大程度上损害了跨上皮电阻，上皮细胞极性，和顶端微绒毛。幽门螺杆菌感染以CagA依赖性方式促进紧密连接中的cortactin/Par1b/ZO-1异常相互作用。人类胃类器官来源的粘膜的感染支持这些观察。因此，我们假设CagA通过劫持cortactin破坏胃上皮细胞的极性，因此Par1b和ZO-1提示了幽门螺杆菌在胃癌发生发展中的新信号通路。
