E3泛素连接酶Nrdp1优先促进TLR介导的Ⅰ型干扰素产生

The E3 Ubiquitin Ligase Nrdp1 "Preferentially" Promotes TLR-mediated Production of Type Ⅰ Interferon

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 in both innate and adaptive immunity.Here we report that Nrdp1,an E3 ubiquitin ligase,inhibited the production of proinflammatory cytokines but increased interferon-β production in Toll-like receptor-triggered macrophages by suppressing adaptor MyD88-dependent activation of transcription factors NF-κB and AP-1 while promoting activation of the kinase TBK1 and transcription factor IRF3.Nrdp1 directly bound and polyubiquitinated MyD88 and TBK1,which led to degradation of MyD88 and activation of TBK1.Knockdown of Nrdp1 inhibited the degradation of MyD88 and the activation of TBK1 and IRF3.Nrdp1-transgenic mice showed resistance to lipopolysaccharide-induced endotoxin shock and to infection with vesicular stomatitis virus.Our data suggest that Nrdp1 functions as both an adaptor protein and an E3 unbiquitin ligase to regulate TLR responses in different ways.