细胞自噬对病原诱导天然免疫细胞因子转录激活信号通路的调控作用

Innate immune response are the initial reactions against pathogens, which induce inflammatory effects through a series of signaling pathways leading to the activation of the cytokines transcription, as well as the mature and secretion of inflammatory factors such as IL-1β. These processes must be properly terminated to maintain immune homeostasis and prevent the organism damage. Macroautophagy, or autophagy is traditionally thought to be a way for cells survival by breaking down cell inclusions in the absence of nutrients. More and more studies have shown that autophagy has a variety of physiological functions. As an important degradation system in cells, autophagy plays an important role in the elimination of pathogens and inhibits the over mature and secretion of inflammatory cytokines by inhibiting the activation of inflammasome. Abnormal autophagy is a direct or indirect cause of immune hyperactivity related diseases. The relationship between autophagy and innate immune signaling pathway has great research value. At present, little is known about the regulation role of autophagy on the innate immune signaling of cytokine transcription induction. In preliminary study, we found that autophagy related proteins mediate the degradation of a key kinase in the innate immune signaling pathway. Using pathogen induced transcription induction of type I interferon and pro-inflammatory factors as the research model, we plan to study the regulatory function and mechanism of autophagy in the innate immune process.

天然免疫是细胞对抗病原刺激的最初反应，通过一系列信号通路激活多种细胞因子转录表达，以及激活炎症因子前体蛋白的成熟分泌来引发抗病原体炎症效应。这一过程必须适度终止以维持免疫稳态，避免细胞及机体的损伤。自噬传统上被认为是细胞在营养匮乏情况下分解细胞内含物的自救途径。越来越多的研究证据显示自噬具有多样的生理功能。作为细胞内重要的降解体系，自噬除了发挥清除病原体的作用，还通过抑制炎症体的活化预防炎症因子前体蛋白过度成熟分泌。充分了解自噬信号途径与天然免疫信号途径间的联系具有重要的研究价值。目前关于自噬对天然免疫细胞因子转录激活信号通路的调控作用了解不足。在前期研究中我们发现自噬相关蛋白通过介导天然免疫信号通路关键激酶的降解负调节I型干扰素的表达。我们计划以病原诱导I型干扰素及促炎症因子转录激活的信号通路为模型，研究细胞自噬在天然免疫过程中发挥的调控作用及作用机制。

本课题计划研究细胞自噬在病原诱导细胞因子转录活化的信号通路中的调控作用，从而进一步了解细胞自噬与天然免疫信号途径之间的联系。我们发现自噬信号通路中ULK1/DENND3/Rab12负调节病原RNA以及DNA诱导的I型干扰素的表达，其调控作用的靶点是在天然免疫的多条信号通路交汇点发挥关键作用的激酶TBK1，通过介导TBK1发生自噬依赖性降解发挥作用。研究结果为天然免疫的控制机制以及天然免疫与自噬之间的“crosstalk”提供新线索。此外在项目资助下，我们发现并报道了病原DNA激活天然免疫的重要枢纽蛋白STING的新的调控机制，人类Ⅲ型家族性/获得性噬血细胞性淋巴组织细胞增生症（Familial / Acquired hemophagocytic lymphohistiocytosis 3 ，FHL3 / HLH）相关基因UNC13D，其功能缺陷促进内质网上STING的寡聚化，从而提高了细胞本底以及病原DNA诱导的炎症因子的表达水平，而STING小分子抑制剂可以有效降低炎症因子水平。这一研究结果为FHL3相关疾病的机制及治疗提供了新线索。