血管生成因子AGGF1在机体抗DNA病毒天然免疫中的作用及调控机制

The innate immune system could efficiently recognize the microbial breaking through host’s tissue barrier and activate immune system to kill the pathogenic microbial. If innate immune response continues to activate, it will lead to autoimmune diseases. Although IFN-I signal pathway has been extensively studied, it is largely unknown how the pathway is regulated. We have found that angiogenesis factor AGGF1 is a negative regulator of DNA-viral infection triggered innate immunity and AGGF1 could interact with STING and/or TBK1. In the study, we hypothesize AGGF1 may regulate host's innate immune responses through affecting the function of STING and/or TBK1. In order to verify this hypothesis, we will uncover the important role of AGGF1 in DNA-viral infection triggered innate immunity and explore its specific regulatory mechanisms, such as whether AGGF1 can impact the important processes of IFN-I signal pathway and which gene is the target of AGGF1. This study not only uncover a new function of AGGF1 gene but also find a new regulatory factor for innate immunity. This help us to understand the mechanism of innate immune response and provide new target for antiviral and autoimmune diseases.

天然免疫能够迅速识别并激活相应的免疫反应，抵御病原微生物的入侵。但其过度激活则与多种自身免疫疾病密切相关。目前，对于机体抗DNA病毒的免疫反应调控知之甚少，许多关键的信号转导和调节分子有待发现及深入研究。本课题前期研究发现，AGGF1参与由胞浆DNA诱导的天然免疫反应的负性调控，并与免疫信号通路中关键核心蛋白STING和TBK1存在相互作用。因此，我们推测：AGGF1通过影响核心蛋白STING和TBK1的功能来调控由胞浆DNA诱导的天然免疫反应。本课题将从分子、细胞和动物水平，首先明确AGGF1在抗DNA病毒天然免疫中的作用，进而探讨其调控的分子机制，包括AGGF1是否影响免疫应答中的标志性事件；AGGF1是通过调控哪些蛋白发挥作用等。本研究既是对AGGF1基因功能新的补充，同时又找到新的调控因子，为机体抗DNA病毒和自身免疫性疾病提供新的靶点及理论依据。

天然免疫能够迅速识别并激活相应的免疫反应，抵御病原微生物的入侵。但其过度激活则与多种自身免疫疾病密切相关。目前，对于机体抗DNA病毒的免疫反应调控知之甚少，许多关键的信号转导和调节分子有待发现及深入研究。本课题首次揭示了AGGF1在DNA病毒诱导的细胞免疫反应中双重作用。一方面，AGGF1通过与STING相互作用，抑制STING的磷酸化，进而影响IRF3的磷酸化和入核，从而负性调控IFN-β的表达。另一方面，AGGF1通过调控properdin的表达，影响HSV-1病毒对细胞的感染和病毒的复制。本研究既是对AGGF1基因功能新的补充，同时又找到IFN-β信号通路新的调控因子，为机体抗DNA病毒和自身免疫性疾病提供新的靶点及理论依据。