E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation
E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation
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E3 连接酶 WWP2 通过靶向 TRIF 泛素化和降解来负调节 TLR3 介导的先天免疫反应
DOI：
10.1073/pnas.1220271110
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发表时间：
2013-03-26
影响因子：
11.1
通讯作者：
Wang, Yan-Yi
中科院分区：
文献类型：
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作者：
Yang, Yan;Liao, Bing;Wang, Yan-Yi
Toll样受体3（TLR 3）识别病毒双链RNA触发转录因子NF-κ B和干扰素调节因子3的激活，导致I型干扰素和促炎细胞因子的诱导。含TIR结构域的衔接子诱导干扰素-β（TRIF）是TLR 3介导的信号传导所需的衔接子蛋白。在这里，我们确定了E3泛素连接酶WW结构域的蛋白2（WWP 2）作为TRIF相关蛋白的生化纯化。WWP 2介导TLR 3活化后TRIF的K48连接的泛素化和降解。WWP 2的过表达抑制了TLR 3介导的NF-κ B和干扰素调节因子3的激活，而WWP 2的敲低则具有相反的作用。我们产生了Wwp 2缺陷小鼠，以进一步研究Wwp 2在先天免疫应答中的作用。一致地，响应于TLR 3配体poly（I：C）的IFN-β、CCL 5、TNF α和IL-6的产生在Wwp 2（-/-）巨噬细胞中升高，并且Wwp 2缺陷小鼠表现出比对照同窝出生小鼠对poly（I：C）诱导的死亡的易感性增加。我们的研究结果表明，WWP 2负调控TLR 3介导的先天免疫和炎症反应，通过靶向TRIF的泛素化和降解。
Recognition of viral double-stranded RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-kappa B and interferon regulated factor 3, leading to induction of type I interferons and proinflammatory cytokines. TIR-domain-containing adapter-inducing interferon-beta (TRIF) is an adapter protein required for TLR3-mediated signaling. Here we identified the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2) as a TRIF-associated protein by biochemical purification. WWP2 mediated K48-linked ubiquitination and degradation of TRIF upon TLR3 activation. Overexpression of WWP2 inhibited TLR3-mediated NF-kappa B and interferon regulated factor 3 activation, whereas knockdown of WWP2 had opposite effects. We generated Wwp2-deficient mice to further investigate the roles of Wwp2 in innate immune responses. Consistently, production of IFN-beta, CCL5, TNF alpha, and IL-6 in response to the TLR3 ligand poly(I:C) was elevated in Wwp2(-/-) macrophages and Wwp2-deficient mice exhibited increased susceptibility to poly(I:C)-induced death than the control littermates. Our findings suggest that WWP2 negatively regulates TLR3-mediated innate immune and inflammatory responses by targeting TRIF for ubiquitination and degradation.