Src在模式识别受体介导的I型干扰素反应中的作用及机制研究

Pattern Recognition Receptors (PRRs) have critical roles of initiating innate immunity in host defense against infection by detecting conserved components of invading microbial pathogens. Over-activation of PRRs induced excessive production of proinflammatory cytokines and type I interferon, which might induce pathological damage. Studies have shown that immunoreceptor tyrosine-based activation motif (ITAM)-based signaling functions in regulating PRRs signaling. The Src family kinases are nonreceptor tyrosine kinases that regulate diverse arrays of cellular responses and the key role in ITAM-based signaling pathway.But the detailed mechanisms by which Src signaling in innate immunity is fine tuned remain unclear. Our preliminary data shows that Src inhibitor could increase IRF3 activation and I type IFN preoduction induced by PRRs ligands, the relative mechaniams involved E3 liages c-cbl and cbl-c ubiquitin IRF3 promoted by Src. This proposal investigates the detailed molecular mechanisms underlying Src-regulated production of type I IFNs in PRRs mediated innate immune response. It will be helpful to understand deeply the mechanism of innate immune defence against pathogens infection.

TLR、RLR和NLR三类模式识别受体（PRRs）是免疫细胞识别病原保守成分启动固有免疫的重要分子，其活化程度影响自身免疫病、肿瘤等多种疾病的发生发展,对于PRRs信号调控机制的研究是固有免疫研究领域的热点。最新的研究证明PRRs与含ITAM的免疫受体之间存在密切地信号交叉调控。非受体型酪氨酸蛋白激酶Src在含ITAM基序的免疫受体所介导的信号传导过程中是关键的调控分子，而其在PRRs介导的固有免疫中的作用及分子机制尚未阐明。我们前期研究发现，在小鼠原代腹腔巨噬细胞中Src抑制剂能增强TLR和RLR配体刺激诱导的IRF3活化以及I型干扰素的产生，可能机制涉及Src活化增强了泛素E3连接酶cbl-b和c-cbl对IRF3的泛素化。本课题拟进一步研究非受体型酪氨酸蛋白激酶Src调控PRRs介导的I型干扰素反应信号途径与效应的分子机制，为感染性疾病防治新方法的建立提供新的候选靶分子。

固有免疫系统组成了抗感染的第一道防线，机体识别入侵的病原体后， PRRs通过活化下游的信号通路启动免疫应答，进而分泌I型干扰素等细胞因子清除病原体。转录因子IRF3的激活是诱导I型干扰素的产生和启动细胞抗感染免疫反应的关键。本项目发现非受体蛋白酪氨酸激酶Src在模式识别受体介导的IRF3的活化及I型干扰素产生中的调控作用，明确非受体蛋白酪氨酸激酶Src活化能够促进c-Cbl的活性并增强其与IRF3的结合能力，证实E3泛素酶c-Cbl介导病毒诱导的IRF3的K48泛素化及蛋白酶体降解，揭示了IRF3蛋白转录后修饰的新机制，阐明非受体型酪氨酸蛋白激酶调控PRR介导的I型干扰素反应信号途径与效应的部分分子机制，为机体抗感染免疫反应防治新分子靶点的寻找和证实提供实验基础。