TOB1调控I型干扰素表达及其在抗病毒感染中的作用

The production of type I interferons is the key for body to clear early virus invasion; However, excessive responses will injure body, causing various autoimmune diseases. So the regulating research to the process is important for theoretical and practical significance. We previously found viral infection inducted TOB1 expression; TOB1 knockdown or knockout could enhance the production of type I interferons and the downstream signal pathway activation; suggesting TOB1 negatively regulated antiviral innate immune response. We further found TOB1 specially binded to IFN regulatory factor 3 (IRF3) and inhibited its transcriptional activity; TOB1 also binded to histone deacetylases 8 (HDAC8). Therefore, we hypothesize that TOB1 targets at IRF3 and HDAC8, recruiting histone deacetylases 8 (HDAC8) to IFN-β gene promotor region, reducing promotor histone acetylation level by its deacetylase function, so that inhibiting type I interferons transcription and subsequent antiviral immune response.our study will use TOB1 knockout mice and various molecular biology and immunology technologies to explor TOB1 regulates type I interferons production and its function in antiviral innate immune response, clarifying molecular mechanism; and provide theoretical foundation and drug targets for Virus infection disease treatment and prevention.

I型干扰素的产生对于机体早期清除入侵病毒至关重要；其过度表达又会损伤机体，导致自身免疫性疾病的发生。因此，对该过程的调控研究具有重要的理论和现实意义。我们发现病毒感染可诱导TOB1表达；TOB1干扰或缺陷可促进I型干扰素产生和下游通路活化；提示TOB1可反馈性抑制抗病毒天然免疫反应。进一步发现TOB1特异性结合IRF3，抑制其转录活性；TOB1结合与去乙酰化酶家族分子HDAC8。因此，我们提出假设：TOB1通过结合IRF3和HDAC8，将HDAC8募集至IFN-β基因启动子区，通过其去乙酰化酶活性，下调I型干扰素基因启动子区组蛋白乙酰化水平，从而抑制I型干扰素转录和后续抗病毒免疫反应。本项目拟利用TOB1基因敲除小鼠和多种分子生物学、免疫学技术，探讨TOB1对I型干扰素的表达调控及其在抗病毒天然免疫反应中的作用，并阐明分子机制；以期为病毒感染性疾病的预防和治疗提供理论依据和潜在药物靶点。

干扰素调节因子IRF3是诱导I型干扰素 (IFN-α/β)表达并启动抗病毒免疫反应的关键转录因子。然而，病毒阻断IRF3介导的抗病毒免疫反应和促进免疫逃逸的潜在机制仍不清楚。在本项研究中，我们发现病毒感染显著诱导TOB1与IRF3相互作用并与Ifnb1的启动子区域结合。进一步研究我们发现TOB1破坏IRF3与Ifnb1 启动子区域结合的同时募集组蛋白去乙酰化酶 8 (HDAC8)至Ifnb1 启动子区域来抑制Ifnb1转录。因此，TOB1抑制了病毒感染巨噬细胞中IRF3介导的IFN-β表达。Tob1缺陷促进抗病毒免疫反应并抑制病毒在体内的复制。综上所述，我们将 TOB1 鉴定为宿主抗病毒固有免疫反应的反馈抑制因子，并揭示了病毒免疫逃逸的机制。