Inhibition of the NF-κB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo
Inhibition of the NF-κB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo
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DOI：
10.1128/jvi.01956-05
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发表时间：
2006-06-01
影响因子：
5.4
通讯作者：
Arvin, Ann M.
中科院分区：
文献类型：
--
作者：
Jones, Jeremy O.;Arvin, Ann M.
水痘-带状疱疹病毒(VZV)是一种引起水痘和带状疱疹的甲型疱疹病毒。利用人细胞DNA芯片，我们发现在VZV感染的成纤维细胞中，许多核因子-kappa B(NF-kappa B)反应基因下调，这表明VZV感染抑制了NF-kappa B途径。这一途径的激活会引起细胞抗病毒反应，包括产生α/β干扰素、细胞因子和其他限制病毒感染的蛋白质。在这些实验中，我们证实了VZV干扰体内感染的SCIDhu小鼠异种皮肤移植的成纤维细胞和分化的表皮细胞中的核因子-kappaB的激活。VZV感染成纤维细胞引起典型的核因子-kappaB家族成员p50和p65的一过性核转位。在依赖于传染性VZV存在的过程中，这些蛋白迅速隔离在VZV感染细胞的细胞质中。核因子-kappa B蛋白的排除与I kappa Bα的持续存在有关，I kappa Bα结合p50和p65并阻止它们的核积累。即使蛋白被磷酸化和泛素化，根据对该蛋白特有的高分子量形式的检测，I kappa Bα的水平也没有下降，并且26S蛋白酶体在VZV感染的细胞中仍然具有功能。VZV感染还抑制了因成纤维细胞暴露于肿瘤坏死因子α而导致的Ikappa Bα的特征性降解。正如预期的那样，单纯疱疹病毒1型导致了NF-kappa B蛋白的持续性核转位，这已被证明有助于其复制，而VZV感染的进展没有持续的NF-kappa B核定位。我们认为VZV已经进化出一种机制，通过将NF-kappa B蛋白隔离在细胞质中来限制宿主细胞的抗病毒防御，这一策略似乎在疱疹病毒中是独一无二的。
Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella and herpes zoster. Using human cellular DNA microarrays, we found that many nuclear factor kappa B (NF-kappa B) -responsive genes were down-regulated in VZV-infected fibroblasts, suggesting that VZV infection inhibited the NF-kappa B pathway. The activation of this pathway causes a cellular antiviral response, including the production of alpha/beta interferon, cytokines, and other proteins that restrict viral infection. In these experiments, we demonstrated that VZV interferes with NF-kappa B activation in cultured fibroblasts and in differentiated epidermal cells in skin xenografts of SCIDhu mice infected in vivo. VZV infection of fibroblasts caused a transient nuclear translocation of p50 and p65, the canonical NF-kappa B family members. In a process that was dependent upon the presence of infectious VZV, these proteins rapidly became sequestered in the cytoplasm of VZV-infected cells. Exclusion of NF-kappa B proteins from nuclei was associated with the continued presence of I kappa B alpha, which binds p50 and p65 and prevents their nuclear accumulation. I kappa B alpha levels did not diminish even though the protein became phosphorylated and ubiquitinated, as determined based on detection of the characteristic high-molecular-weight form of the protein, and the 26S proteasome remained functional in VZV-infected cells. VZV infection also inhibited the characteristic degradation of I kappa B alpha that is induced by exposure of fibroblasts to tumor necrosis factor alpha. As expected, herpes simplex virus 1 caused the persistent nuclear translocation of NF-kappa B proteins, which has been shown to facilitate its replication, whereas VZV infection progressed without persistent NF-kappa B nuclear localization. We suggest that VZV has evolved a mechanism to limit host cell antiviral defenses by sequestering NF-kappa B proteins in the cytoplasm, a strategy that appears to be unique among the herpesviruses.