Varicella-Zoster Virus Immediate-Early Protein ORF61 Abrogates the IRF3-Mediated Innate Immune Response through Degradation of Activated IRF3
Varicella-Zoster Virus Immediate-Early Protein ORF61 Abrogates the IRF3-Mediated Innate Immune Response through Degradation of Activated IRF3
复制标题
水痘带状疱疹病毒立即早期蛋白 ORF61 通过降解激活的 IRF3 消除 IRF3 介导的先天免疫反应
DOI：
10.1128/jvi.05098-11
复制
发表时间：
2011-08
影响因子：
5.4
通讯作者：
Mossman, Karen L.
中科院分区：
文献类型：
--
作者：
Zhu, Huifang;Zheng, Chunfu;Xing, Junji;Wang, Shuai;Li, Shuping;Lin, Rongtuan;Mossman, Karen L.
摘要 水痘 - 带状疱疹病毒（VZV）对宿主体内分化细胞的感染以及潜伏状态的建立，很可能需要逃避先天免疫并限制抗病毒细胞因子的分泌。在此我们报告，其即刻早期蛋白OR （这里原文“OR”之后似乎内容不完整）
ABSTRACT Varicella-zoster virus (VZV) infection of differentiated cells within the host and establishment of latency likely requires evasion of innate immunity and limits secretion of antiviral cytokines. Here we report that its immediate-early protein ORF61 antagonizes the beta interferon (IFN-β) pathway. VZV infection down-modulated the Sendai virus (SeV)-activated IFN-β pathway, including mRNA of IFN-β and its downstream interferon-stimulated genes (ISGs), ISG54 and ISG56. Through a primary screening of VZV genes, we found that ORF61 inhibited SeV-mediated activation of IFN-β and ISRE (IFN-stimulated response element) promoter activities but only slightly affected NF-κB promoter activity, implying that the IFN-β pathway may be blocked in the IRF3 branch. An indirect immunofluorescence assay demonstrated that ectopic expression of ORF61 abrogated the detection of IRF3 in SeV-infected cells; however, it did not affect endogenous dormant IRF3 in noninfected cells. Additionally, ORF61 was shown to be partially colocalized with activated IRF3 in the nucleus upon treatment with MG132, an inhibitor of proteasomes, and the direct interaction between ORF61 and activated IRF3 was confirmed by a coimmunoprecipitation assay. Furthermore, Western blot analysis demonstrated that activated IRF3 was ubiquitinated in the presence of ORF61, suggesting that ORF61 degraded phosphorylated IRF3 via a ubiquitin-proteasome pathway. Semiquantitative reverse transcription-PCR (RT-PCR) analysis demonstrated that the level of ISG54 and ISG56 mRNAs was also downregulated by ORF61. Taken together, our results convincingly demonstrate that ORF61 down-modulates the IRF3-mediated IFN-β pathway by degradation of activated IRF3 via direct interaction, which may contribute to the pathogenesis of VZV infection.
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