The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense.
The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense.
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DOI：
10.1084/jem.20021652
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发表时间：
2003-02-03
影响因子：
15.3
通讯作者：
O'Neill, LAJ
中科院分区：
文献类型：
--
作者：
Harte, MT;Haga, IR;Maloney, G;Gray, P;Reading, PC;Bartlett, NW;Smith, GL;Bowie, A;O'Neill, LAJ
Toll样受体（TLR）在对病原体的先天免疫应答中是至关重要的，因为它们识别并应答病原体相关的分子模式，这导致细胞内信号传导途径的激活和基因表达的改变。牛痘病毒（VV），用于接种天花疫苗的痘病毒，编码拮抗宿主抗病毒防御重要成分的蛋白质。在这里，我们表明VV蛋白A52 R通过多种TLR（包括最近鉴定的病毒RNA受体TLR 3）阻断转录因子核因子κB（NF-κB）的激活。A52 R与白细胞介素1受体相关激酶2（IRAK 2）和肿瘤坏死因子受体相关因子6（TRAF 6）相关，这两种蛋白在TLR信号转导中很重要。此外，A52 R可以破坏含有这些蛋白质的信号复合物。在小鼠鼻内感染模型中，与野生型和回复突变体对照相比，缺乏A52 R基因的病毒缺失突变体减弱。本研究揭示了VV抑制宿主免疫的新机制。我们证明病毒禁用的TLR，提供了进一步的证据，这个家庭的受体在抗病毒反应中的重要作用。
Toll-like receptors (TLRs) are crucial in the innate immune response to pathogens, in that they recognize and respond to pathogen associated molecular patterns, which leads to activation of intracellular signaling pathways and altered gene expression. Vaccinia virus (VV), the poxvirus used to vaccinate against smallpox, encodes proteins that antagonize important components of host antiviral defense. Here we show that the VV protein A52R blocks the activation of the transcription factor nuclear factor κB (NF-κB) by multiple TLRs, including TLR3, a recently identified receptor for viral RNA. A52R associates with both interleukin 1 receptor–associated kinase 2 (IRAK2) and tumor necrosis factor receptor–associated factor 6 (TRAF6), two key proteins important in TLR signal transduction. Further, A52R could disrupt signaling complexes containing these proteins. A virus deletion mutant lacking the A52R gene was attenuated compared with wild-type and revertant controls in a murine intranasal model of infection. This study reveals a novel mechanism used by VV to suppress the host immunity. We demonstrate viral disabling of TLRs, providing further evidence for an important role for this family of receptors in the antiviral response.
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