RNF125调控NLRP3炎症小体的分子机制研究

项目名称： RNF125调控NLRP3炎症小体的分子机制研究

项目编号： No.31470850

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 何湘

作者单位： 中国人民解放军军事科学院军事医学研究院

项目金额： 80万元

中文摘要： 炎症小体是宿主固有免疫的重要组成部分，其适度激活对清除病原微生物等损伤起到重要作用，但是过度激活会导致多种组织、器官的伤害，因此炎症小体复合物的活性需要精确调控。前期工作中，我们通过酵母双杂交筛选到一个负调控I型干扰素的E3连接酶RNF125可能与NLRP3发生相互作用，并通过免疫共沉淀证明了二者的相互作用。初步研究还发现RNF125促进NLRP3 K63连接的泛素化，增加NLRP3稳定性，促进NLRP3炎症小体IL-1β分泌的功能；而RNF125泛素化酶活性缺失则丧失了以上功能。综上，RNF125很有可能以NLRP3为其E3连接酶底物参与调控炎症小体的激活。接下来我们拟利用体内、体外细胞及动物模型，确立RNF125与NLRP3的相互作用及其生理学意义，揭示RNF125调控炎症小体信号通路的分子机制，探索固有免疫不同信号通路间交互作用的机理，并有可能为抗炎及抗感染药物开发提供潜在的靶点。

中文关键词： 炎症小体；固有免疫；蛋白相互作用；信号通路

英文摘要： Inflammasomes are key signaling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β(IL-1β) and interleukin-18 (IL-18). Stringent control of inflammasome signaling pathway is important for keeping immunological balance, yet the regulatory mechanisms responsible for its tight regulation are still poorly understood. Here we found RNF125, an E3 ligase that inhibit type I interferon (IFN) signaling pathway by targeting RIG-1 for degradation, was required for the optimal activation of IL-1β production. Specially, NLRP3 is speculated as a candidate substrate of E3 ligase RNF125 since the mutation of RNF125 ubiquitin ligase activity lose its ability to active NLRP3 inflammasome. Taken together, we would like to further explore the interaction of RNF125 with NLRP3 and their biological significance. We believe our investigation of RNF125 on NLRP3 inflammasome pathway will not only help us to further understand the mechanisms responsible for crosstalk between inflammasome and type I IFN innate immune pathway but will also provide novel therapeutic target for preventing or treating patients with inflammatory and/or infectious diseases.

英文关键词： Inflammasome;Innate immune;Protein-protein interaction;Signaling pathway