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E3泛素连接酶对于固有免疫和获得性免疫非常重要。我们发现E3泛素连接酶Nrdp1通过抑制MyD88依赖的转录因子NF-κB和AP-1的活性并促进激酶TBK1和转录因子IRF3的活性,进而抑制Toll样受体诱发的促炎症细胞因子的产生,但增加了巨噬细胞的干扰素-β分泌。Nrdp1可以直接结合并将MyD88和TBK1多泛素化,进而导致MyD88的降解和TBK1的活化。敲低Nrdp1的表达可抑制MyD88的降解以及TBK1和IRF3的活化。Nrdp1转基因小鼠表现出对脂多糖诱导内毒素休克和对疱疹口炎病毒感染的抗性。上述结果提示,Nrdp1同时具有接头蛋白和E3泛素连接酶的功能,可通过不同的方式调节TLR反应。
E3 ubiquitin ligases are important for both innate and adaptive immunity. We found that Nrdp1, an E3 ubiquitin ligase, inhibits Toll-like receptor-induced proinflammatory cytokines by inhibiting the activity of MyD88-dependent transcription factors NF-κB and AP-1 and promoting the activity of kinase TBK1 and transcription factor IRF3, But increases the secretion of interferon-β by macrophages. Nrdp1 directly binds and multi-ubiquitinates MyD88 and TBK1, leading to the degradation of MyD88 and the activation of TBK1. Knockdown of Nrdp1 expression inhibited MyD88 degradation and activation of TBK1 and IRF3. Nrdp1 transgenic mice showed resistance to lipopolysaccharide-induced endotoxic shock and herpes simplex virus infection. The above results suggest that Nrdp1 has the function of linker protein and E3 ubiquitin ligase and can regulate TLR responses in different ways.