天然免疫作为机体抗病毒感染的"第一道防线"，对于病毒的识别和清除起着至关重要的作用。前期工作发现，病毒感染可诱导TRIM26蛋白的表达以及核转位；TRIM26过表达可显著抑制IFN-β的活化，并促进VSV病毒的复制，而siRNA干扰可促进IFN-β的生成，抑制VSV病毒复制；TRIM26转基因鼠的原代巨噬细胞，活化后IFN-β的表达大大降低，而VSV的复制显著增高。这些结果提示，TRIM26可作为反馈调节因子调控抗病毒天然免疫反应。本课题拟利用巨噬细胞、HEK293 等细胞和TRIM26转基因鼠，结合各种分子技术手段深入探讨TRIM26在抗病毒天然免疫中的功能，并通过研究TRIM26与抗病毒信号转导途径中关键分子的相互作用，揭示其作用的分子机制。本研究首次探讨TRIM26在抗感染天然免疫中的功能及其作用机制，将为抗病毒天然免疫应答的调控机制提供新思路，以及抗感染药物的设计提供新的潜在靶点。

Innate immunity is the first line against virus infection. After viral infection, the viral molecules such as RNA and DNA can be recognized by innate immune receptors including TLR, RLR and DNA sensors, leading to the production of proinflammatory cytokines and interferons, which are essential for the elimination of viral infection. Except for the expression of proinflammatory cytokines and type I interferons, the innate immune system also expresses varieties of feedback molecules after virus infection. These molecules are thought to regulate the secretion of proinflammatory cytokines and type I interferons and to prevent excessive activation of the innate immune responses. We have previously demonstrated that TLR3/4 activation by LPS or poly(I:C) induced the expression of tripartite motif protein 26 (TRIM26) in macrophages. TRIM26 expression was also induced by Sendai virus (SeV) infection. Importantly, TRIM26 protein was distributed to nucleus after SeV and vesicular stomatitis virus (VSV) infection or IFN-β stimulation. These data indicate that TRIM26 may play an important role in the regulation of antiviral innate immune responses. Indeed, we found that TRIM26 overexpression attenuated TLR3-, TLR4-, RLR- and dsDNA sensor-induced IFN-β promoter activation, while, VSV replication was increased upon TRIM26 overexpression. In contrast, siRNA knockdown of TRIM26 expression increased IFN-β production and decreased VSV replication. Decreased IFN-β production and increased VSV replication was also found in primary macrophages from TRIM26 transgenic mice, compared to the macrophages from WT mice. In this project, we propose to use TRIM26 transgenic mice and various of cells including macrophages and HEK293 cells to investigate the functions of TRIM26 in the producton of IFN-β and antiviral immune responses. We will also use varieties of molecular techniques such as Dual-Luciferase Reporter Assay, co-immunoprecipitation, in vitro and in vivo ubiquitination to identify the targets that are regulated by TRIM26. Finally, we will figure out how the targets were regulated by TRIM26. TRIM26 is located in the MHC class I coding region, but the function of TRIM26 in the immune regulation is not known. Our study is the first to explore the functions of TRIM26 on the reguation of innate immune resonses and may provide a new threputic target for the antiviral drug design. Given that TRIM26 expression and nuclear translocation was induced by virus infection, our study may provide some new concept of virus-host interaction and new mechanisms for the virus invasion of the innate immune system.