TRIM9负调控抗病毒天然免疫反应的分子机制研究

The signaling transduction and regulation mechanism of virus induced type I interferon production and inflammatory response are research hotspots of immunology in recent years. The processes of pathogen recognition and signaling transduction are precisely regulated to guarantee homeostasis of the immune system. Studies in the past years suggested that the TRIM family members are highly related with innate immunity. However, the functions and underlying mechanisms of most TRIMs are still poorly understood. In our previous studies, we identified TRIM9 as a negative regulator of antiviral response from over 40 TRIMs. Over expression of TRIM9 inhibited SeV induced type I interferon production in a dose-dependent manner, whereas knockdown of TRIM9 potentiated SeV induced production of type I interferon as well as inflammatory cytokines. In this project, we will examine the effects of TRIM9 on different virus-triggered cellular antiviral response and virus replication. We will try to identify the target protein of TRIM9 by means of coimmunoprecipitation, immune purification and mass spectrum analysis, and so on. Further more, we will explore the molecular mechanism of TRIM9-mediated regulation of virus- stimulated type I interferon and inflammatory response. This research will provide new clues for understanding of TRIMs-mediated regulation of the innate immunity, and contribute for elucidation the precise regulation mechanism of antiviral innate immunity.

病毒诱导I型干扰素表达和炎症反应的信号转导和调控机制是免疫学领域的研究热点之一。天然免疫系统存在精密的调控机制，以维持机体免疫反应的稳态。近年的研究表明，TRIM家族蛋白与抗病毒天然免疫密切相关，但大多数TRIMs在抗病毒天然免疫中的功能和机制还不清楚。在前期的研究中，我们从40多个TRIM中筛选到一个负调控病毒诱导IFN-beta表达的分子TRIM9。过量表达TRIM9剂量依赖性地抑制SeV诱导的I型干扰素表达，而RNAi下调TRIM9的表达能够显著增强SeV诱导的I型干扰素和炎症因子的表达。本项目将深入研究TRIM9在各种模式病毒诱导的细胞抗病毒反应中的功能；通过免疫共沉淀、质谱鉴定等方法鉴定TRIM9的靶标蛋白，并揭示TRIM9调控病毒诱导I型干扰素表达和炎症反应的分子机制。该项研究有助于完善对TRIMs调节天然免疫的分子机制的认识，并为揭示抗病毒天然免疫的精密调控机制做出贡献。

病毒诱导I型干扰素表达和炎症反应的信号转导和调控机制是免疫学领域的研究热点之一。宿主通过模式识别受体识别病毒感染产生的保守成分，通过一系列信号转导途径诱导I型干扰素的产生。I型干扰素通过诱导下游抗病毒蛋白的表达，抑制病毒的复制或者诱导被感染细胞的凋亡，引起抗病毒天然免疫应答。近年的研究表明，TRIM家族蛋白与抗病毒天然免疫密切相关，但大多数TRIMs在抗病毒天然免疫中的功能和机制还不清楚。通过系统筛选40多个TRIM家族蛋白，我们发现多个新的影响病毒诱导I型干扰素表达的TRIM蛋白，包括TRIM9和TRIM26。在项目执行过程中，TRIM9的功能被抢先报道（Negative regulation of NF-kB activity by brain-specific TRIpartite Motif protein 9，Nature Communications, 2014)，因此我们将研究目标调整为研究TRIM26在细胞抗病毒反应中的功能和机制。TRIM26以不依赖于泛素化修饰的方式与TBK1相互作用，而依赖于其自身泛素化修饰介导其与NEMO相互作用，从而介导TBK1和NEMO的相互作用，促进TBK1的活化。TRIM26是RIG-I样受体介导信号通路中TBK1活化的重要桥梁蛋白，在RNA病毒诱导的抗病毒反应中发挥正调控作用。该研究结果发表在JMCB杂志上。该项研究有助于完善对TRIM家族蛋白调节天然免疫的分子机制的认识，并为揭示抗病毒天然免疫的精密调控机制做出贡献。