Herpesvirus tegument protein activates NF-κB signaling through the TRAF6 adaptor protein
Herpesvirus tegument protein activates NF-κB signaling through the TRAF6 adaptor protein
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DOI：
10.1073/pnas.0801617105
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发表时间：
2008-08-12
影响因子：
11.1
通讯作者：
Knipe, David M.
中科院分区：
文献类型：
--
作者：
Liu, XueQiao;Fitzgerald, Katherine;Knipe, David M.
病毒通过将病毒粒子蛋白运送到细胞内和通过病毒蛋白的从头表达来重塑宿主细胞以优化其复制。HSV颗粒包含几种蛋白质，它们为宿主细胞为病毒复制做好准备，包括VP16转录激活蛋白和病毒粒子宿主关闭蛋白。单纯疱疹病毒感染通过Toll样受体(TLR)2和非TLR途径激活核因子-kappa B途径，而核因子-kappa B活性是病毒有效复制所必需的。在单纯疱疹病毒蛋白质组的筛选中，我们观察到单纯疱疹病毒U(L)37被膜蛋白以TLR2不依赖的方式激活核因子-kappaB信号。UL37在转基因细胞中的表达导致报告基因和内源性IL-8基因的I kappa B降解和激活。这种激活需要肿瘤坏死因子受体相关因子6(TRAF6)，而UL37含有一个TRAF6结合域，这是与TRAF6相互作用和激活NF-kappa B所必需的。编码UL37的突变病毒的TRAF6结合位点发生变化，在感染的早期阶段显示NF-kappa B的激活减少。因此，HSV UL37病毒粒子结构蛋白可通过TRAF6激活核因子-kappaB。核因子-kappa B被病毒粒子被膜蛋白激活，在病毒进入宿主细胞时被输送到细胞质中，这是病毒激活这一途径的机制。
Viruses remodel the host cell to optimize their replication both by delivery of virion proteins into the cell and by de novo expression of viral proteins. The HSV particle contains several proteins that function to prepare the host cell for viral replication, including the VP16 transcriptional activator protein and virion host shutoff protein. HSV infection activates NF-kappa B pathways through Toll-like receptor (TLR) 2 and non-TLR pathways, and NF-kappa B activity is required for efficient viral replication. In a screen of the HSV proteome, we observed that the HSV U(L)37 tegument protein activates NF-kappa B signaling in a TLR2-independent manner. Expression Of UL37 in transfected cells leads to I kappa B degradation and activation of both reporter genes and the endogenous IL-8 gene. This activation requires TNF receptor-associated factor 6 (TRAF6), and UL37 contains a TRAF6-binding domain that is required for interaction with TRAF6 and activation of NF-kappa B. A mutant virus encoding UL37 with an altered TRAF6-binding site shows reduced NF-kappa B activation in the early phase of infection. Therefore, the HSV UL37 virion structural protein can activate NF-kappa B through TRAF6. Activation of NF-kappa B by a virion tegument protein that is delivered into the host cell cytoplasm during viral entry represents a mechanism for activation of this pathway by a virus.