紧密连接蛋白Occludin在抗RNA病毒天然免疫应答中作用和机制研究

细胞极性封闭蛋白occludin是细胞紧密连接结构的主要组分之一，在上皮组织中细胞极性、细胞间屏障，内皮细胞血管屏障以及疾病如肿瘤、病毒感染起重要作用。近期，封闭蛋白的非紧密连接功能如调控细胞迁移, 细胞粘附和炎症细胞侵润等凸显受到重视。但封闭蛋白在免疫细胞中功能被忽视因其过低表达。本研究组一直关注封闭蛋白与细胞区域化极性功能结构调控。封闭蛋白是否参与病毒诱导免疫细胞功能结构极性化和天然免疫信号调控？我们研究发现封闭蛋白调控免疫细胞天然免疫应答。病毒感染诱导封闭蛋白在巨噬细胞表达显著上调和内吞胞内定位，呈聚集分布。封闭蛋白敲除明显减弱小鼠抗病毒能力和细胞天然免疫反应，显著抑制天然免疫关键转录因子IRF3磷酸化，但不影响TBK1磷酸化，提示封闭蛋白在天然免疫信号通路中新的作用。基于此本项目拟深入探讨封闭蛋白在免疫细胞极性和天然免疫应答调控作用，揭示其在免疫细胞中非紧密连接新功能和机制。

Occludin is one of the main components of cell tight junctions which plays an important role in cell polarity, intercellular barrier, endothelial vascular barrier and diseases such as tumor and virus infection. Recently, the non-tight junction-functions of occludin such as regulating cell migration, cell adhesion and inflammatory cell infiltration, have attracted more and more attention. However, the role of occludin in immune cells is less concered because of its low expression. Our research group has been focusing on the regulation of occludin in regional polarization in cell membrane domain. Are occludin involved in regulating virus-induced immune cell polarization and innate immune response signaling? We found that occludin plays a role in anti-viral innate immune response of macrophage. RNA virus infection induced up-regulation expression and endocytosis of occludin in macrophage occludin deficiency significantly impaired the anti-viral innate immune response in mice. Virus-infection induced phosphorylation IRF3, but TBK1 was significantly inhibited in macrophage, suggesting that occludin plays a novel role in the regulating innate immune response signaling. Based on this project, we intend to further explore the regulatory role of occludin in the polarization and innate immune response of immune cells, by which hopefully it brings some insights to better understand the occludin’s non -tight junction function in immune cells.