FBXO11调控I型干扰素抗病毒免疫信号通路的机制研究

The evolutionarily conserved F-box family of proteins are well known for serving as a key component of SKP1-Cullin1-F-box (SCF) E3 ligase to control the stability of specific substrates, which have significant physiological functions in cell cycle, cell proliferation and death, carcinogenesis and cancer metastasis. In contrast, there is very limited understanding for their roles in innate immunity of host antiviral responses. Through systematic functional screening, we have found F-box family proteins are widely involved in the regulation of type I interferon (IFN-I) signaling in antiviral immunity. FBXO11 is one of the member of this family of proteins that has shown to potently regulate the early activation of IFN-I signaling for inhibiting viral infection and replication in host cells. Our preliminary results revealed that FBXO11 interacts with TANK-Binding Kinase 1 (TBK1) and promotes its phosphorylation, resulting in enhanced Interferon-Regulatory Factor 3 (IRF3) activation and thereby the up-regulation of down-stream genes. In this proposal, we will utilize FBXO11 knock-out cell lines, as well as knock-out mouse models to investigate the physiological effects of this protein in protecting host from viral infection. Further more, we will delineate the pathway and molecular events how FBXO11 enhances TBK1 phosphorylation. Together these studies will help us to unravel the functional mechanism of FBXO11 in potentiating antiviral responses mediated by IFN-I signaling and provide potential therapeutic targets for developing new antiviral drugs.

已知F-box家族蛋白作为E3泛素化连接酶SCF复合物的关键组成部分，通过控制特定蛋白底物的稳定性在细胞周期，细胞增殖与凋亡及肿瘤发生与转移中发挥重要的生理功能。然而，对F-box蛋白在天然免疫宿主抗病毒反应中的作用认识甚少。通过系统的功能筛选，我们发现该家族蛋白广泛地参与I型干扰素抗病毒免疫信号通路的各种调节。其中，FBXO11对I型干扰素通路早期激活产生上调作用而有效地抑制病毒在宿主细胞中的感染和复制。初步研究结果表明FBXO11结合TBK1并促进其磷酸化，导致转录因子IRF3活化程度增强和下游基因表达提高。本项目将利用FBXO11敲除细胞系和FBXO11敲除小鼠模型探究该蛋白在抗病毒免疫中的生理效应，并深入研究FBXO11如何促进TBK1磷酸化的调控机理，以此来阐明FBXO11增强由I型干扰素途径介导抗病毒免疫应答的功能机制，为开发新型抗病毒药物提供潜在的分子靶点。

已知F-box家族蛋白作为E3泛素化连接酶SCF复合物的关键组成部分，通过控制特定蛋白底物的稳定性参与多种重要生理功能调控。然而，对F-box蛋白在天然免疫宿主抗病毒反应中的作用还缺乏系统性研究。前期研究发现FBXO11通过对I型干扰素通路早期激活产生上调作用而有效地抑制病毒在宿主细胞中的感染和复制。进一步机制研究表明FBXO11能够通过与TRAF3互作，从而促进TRAF3的K63泛素化修饰，活化其功能，进而促进其介导的TBK1磷酸化修饰以及下游IRF3磷酸化、二聚化，促进I型干扰素表达分泌，最终通过下游干扰素诱导基因发挥抗病毒作用。本研究还发现NEDD8修饰在FBXO11介导的I型干扰素通路调控中发挥了重要作用，而NEDD8修饰的特异性抑制剂MLN4924可以作为一种I型干扰素信号通路负调控分子，可作为I型干扰素失衡相关疾病候选药物。总之，本项目利用多种工具细胞及小鼠模型探究了FBXO11蛋白在抗病毒免疫中的生理效应，探究FBXO11介导TBK1磷酸化的调控机理，并阐明FBXO11调节I型干扰素途径介导抗病毒免疫应答的分子机制，为开发新型抗病毒药物以及免疫调节剂提供了潜在的分子靶点和理论基础。