The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon
The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon
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DOI：
10.1038/ni.1742
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发表时间：
2009-07-01
影响因子：
30.5
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Wang, Chen;Chen, Taoyong;Cao, Xuetao
E3泛素连接酶在先天性免疫和适应性免疫中都很重要。在这里，我们报告说，Nrdp 1，E3泛素连接酶，抑制促炎细胞因子的产生，但增加干扰素-β的生产在Toll样受体触发的巨噬细胞抑制适配器MyD 88依赖性激活的转录因子NF-κ B和AP-1，同时促进激活的激酶TBK 1和转录因子IRF 3。Nrdp 1直接结合并多聚泛素化MyD 88和TBK 1，这导致MyD 88的降解和TBK 1的活化。Nrdp 1的敲低抑制了MyD 88的降解以及TBK 1和IRF 3的活化。转nrdp 1基因小鼠表现出对脂多糖诱导的内毒素休克和水泡性口炎病毒感染的抵抗力。我们的数据表明，Nrdp 1功能作为一个衔接蛋白和E3泛素连接酶调节TLR反应以不同的方式。
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-beta production in Toll-like receptor-triggered macrophages by suppressing adaptor MyD88-dependent activation of transcription factors NF-kappa B 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.