DNA免疫识别通路cGAS-cGAMP-STING-IFN-β在鸡细胞中功能缺陷的分子基础与调控机制

cGAS-cGAMP-STING-IFN-β（GGSI）是脊椎动物高度保守的DNA识别通路，在抗DNA病毒免疫中发挥关键作用。但我们发现，尽管鸡cGAS可催化合成cGAMP，却不能调控IFN-β激活。为探明原因，本项目将聚焦GGSI通路的枢纽分子，基于结构生物学，解析cGAMP与鸡STING的结合能力和互作机制；基于信号转导，分析cGAMP刺激下鸡STING的激活、修饰、多聚化和胞内转位特征，研究IRF7代偿鸡天然缺失的IRF3参与DNA免疫识别的潜能及机制；基于多组学技术，绘制鸡cGAS、cGAMP介导的DNA免疫识别分子调控网络；基于交互调控网络，探究负调控分子在鸡GGSI通路功能缺陷中的贡献和作用模式。最终系统阐明鸡GGSI通路功能缺陷的分子基础、调控机制以及鸡cGAS的潜在生物学功能。成果将进一步丰富对脊椎动物cGAS功能的认识，为基于天然免疫开展鸡DNA病毒免疫防控提供科学依据。

cGAS-cGAMP-STING-IFN (GGSI) is a highly conservative DNA sensing and signaling pathway in vertebrates that plays a crucial role in anti-DNA virus innate immunity. However, we found that chicken cGAS cannot regulate IFN-beta activation, although it can catalyze the synthesis of 2'3'-cGAMP from ATP and GTP. To explore the reasons, this proposal will focus on the junctional molecules of the GGSI pathway. The binding capability and characteristics of cGAMP and chicken STING will be analyzed based on structural biology; The positive or negative response and the underlying mechanism of chicken STING-IRF7 to cGAMP stimulation will be elucidated by signal transduction strategy; and the contribution to the defective signaling and work model of negative regulatory molecules in chicken GGSI pathway will be explored based on the interactive network. Overall, the work will clarify the molecular basis and regulatory mechanism of the functional defects of the GGSI pathway in chicken. At the same time, using multi-omics techniques, the molecular regulation network mediated by chicken cGAS or cGAMP will be constructed to determine the potential function of cGAS in chicken cells. The results will not only clarify the mechanism of the chicken GGSI pathway defects, but also reveal the novel function of chicken cGAS-cGAMP, which will further enrich the understanding of the function of vertebrate cGAS-cGAMP and provide a scientific basis for antiviral immunity.