特里夫
TLR3型
泛素连接酶
先天免疫系统
泛素
干扰素
生物
信号转导衔接蛋白
细胞生物学
促炎细胞因子
干扰素调节因子
信号转导
转录因子
免疫系统
Toll样受体
炎症
免疫学
生物化学
基因
作者
Yan Yang,Bing Liao,Suyun Wang,Bin Yan,Ying Jin,Hong‐Bing Shu,Yan-Yi Wang
标识
DOI:10.1073/pnas.1220271110
摘要
Recognition of viral double-stranded RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-κB and interferon regulated factor 3, leading to induction of type I interferons and proinflammatory cytokines. TIR-domain-containing adapter-inducing interferon-β (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-κB 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-β, CCL5, TNFα, 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.
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