病毒DNA被细胞质的多个感受器如cGAS等识别后，通过接头蛋白STING活化下游信号通路，诱导抗病毒I型干扰素及炎症因子的表达。这一信号通路受到严格的调控。在前期研究中我们发现YWHAZ参与这一信号转导过程：敲低YWHAZ能抑制STING结合下游信号分子，并显著抑制DNA病毒诱导的抗病毒基因转录，但其具体作用靶点和分子机制尚不清楚。我们为此提出假说：YWHAZ可能通过作用于靶蛋白cGAS和/或STING，促进cGAS-STING介导的抗DNA病毒信号转导，从而推动抗病毒免疫反应。我们将构建YWHAZ基因敲除或敲低的多种人源细胞系和条件敲除小鼠，从分子、细胞和个体水平开展多种实验，探索YWHAZ在抗DNA病毒天然免疫信号转导中的作用靶点，并明确其调控靶分子功能的分子机制。本研究将揭示YWHAZ在抗DNA病毒天然免疫中的作用，为研发抗病毒药物提供新的分子靶标。

Viral DNA can be recognized by cytoplasmic sensors such as cGAS,which initiates innate immune responses through adaptor protein STING. This signalling pathway leading to production of interferons and inflammatory cytokines should be critically regulated. In our preliminary study, we found YWHAZ participated in viral DNA-induced innate immune responses. YWHAZ Knockdown inhibited recruitment of downstream molecules of STING, and significantly suppressed the transcription of antiviral genes induced by DNA virus. But its molecular mechanism is unclear. We hypothesize that YWHAZ targets at cGAS and/or STING, mediates the functions of the target proteins, and promotes the antiviral innate immune response. We will construct several YWHAZ knockout human cell lines and conditional knockout mice, determine the functions and target proteins of YWHAZ in cGAS-STING pathway, and figure out its molecular mechanism. The successful completion of this project will disclose the function of YWHAZ in anti-DNA viral innate immune response, and provide new targets for developing antiviral drugs.