天然免疫与人类的健康、疾病密切相关。天然免疫的不足或过度皆可引起严重的疾病。十几年来人们对天然免疫的研究取得了许多重大突破，可是对来自于病原体基因组DNA（如病毒DNA）所激活的天然免疫应答的机制还很不清楚。我们的前期工作发现了ERIS及ERIS-TBK1-STAT6对于DNA病毒激活的天然免疫反应至关重要，以此为基础，近期又发现多个可能在此通路中起重要作用的新基因。本项目拟围绕这些分子，研究它们在细胞受到DNA病毒感染后引发天然免疫应答中的作用。重点研究1）高尔基体蛋白Z1及其相关蛋白帮助ERIS进行天然免疫应答的机制；2）IRF3特异性K63位泛素化E3连接酶IUK63活化IRF3的分子机制；3）STAT6及其它STATx在天然免疫中的生理作用。本项目不仅能丰富我们对免疫应答及调控的细胞与分子机制的认识，而且可以对设计研究下一代新型抗感染药物提供可能的靶标。

Innate immunity is the first line of defense against microbial invasions via a set of pattern-recognition molecules. Activation of the innate immune system will lead to the induction of inflammatory cytokines and many other effective factors against different pathogens. Malfunction of the innate immunity is involved in a variety of diseases, such as endotoxic shock, IBD and some cancers due to the hypersensitivity of innate immunity, and many immune-deficiency-related diseases due to hyposensitivity of the innate immunity...We have established a powerful cDNA library screening system to search systematically for new genes that play essential roles in the innate immunity. We identified ERIS/ STING/MITA as an essential player in anti-DNA viral innate immunity, and more recently, ERIS-STAT6-TBK1 was also found to play a critical role in controling the expression a set of chemokines for immune cell homing. Using Yeast two hybrid screening, immuno-purification and Mass-spec-based protein identification techniques, we are also interested in identifying new genes participating in the formation of the signal complexes, such as RIG-I/Mda5/MAVS complex, and STING/TBK1 complex, during the activation of the innate immune system...Based on our previous work, we will work on the following aspects of innate immunity:..I. Identification and characterization of a Golgi protein Z1 that regulates ERIS-mediated innate immunity against DNA viral infection...II. Identification and characterization of an E3 ubiquitin ligase required for IRF3 K63-ubiquitination and activation...III. characterization of the physiololigical function of the new defined signaling cascade leading to STAT6 activation and the existance of other ERIS-STATx cascade, as well as the possible function in anti-viral innate immunity.