Herpes Simplex Virus 1-Encoded Tegument Protein VP16 Abrogates the Production of Beta Interferon (IFN) by Inhibiting NF-kappa B Activation and Blocking IFN Regulatory Factor 3 To Recruit Its Coactivator CBP
Herpes Simplex Virus 1-Encoded Tegument Protein VP16 Abrogates the Production of Beta Interferon (IFN) by Inhibiting NF-kappa B Activation and Blocking IFN Regulatory Factor 3 To Recruit Its Coactivator CBP
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单纯疱疹病毒 1 编码的被膜蛋白 VP16 通过抑制 NF-κ B 激活和阻断 IFN 调节因子 3 招募其共激活剂 CBP 来消除 β 干扰素 (IFN) 的产生
DOI：
10.1128/jvi.01440-13
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发表时间：
2013
影响因子：
5.4
通讯作者：
Zheng Chunfu
中科院分区：
文献类型：
--
作者：
Xing Junji;Ni Liwen;Wang Shuai;Wang Kezhen;Lin Rongtuan;Zheng Chunfu
宿主细胞激活先天免疫信号通路以防御入侵的病原体。为了在受感染的宿主体内生存，病毒进化出了复杂的策略来对抗宿主的免疫反应。疱疹病毒，包括 1 型单纯疱疹病毒 (HSV-1)，具有较大的基因组，因此能够编码大量调节宿主先天免疫反应的蛋白质。在这里，我们定义了 HSV-1 外皮蛋白 VP16 在抑制 β 干扰素 (IFN-β) 产生中的贡献。 VP16 被证明能够显着抑制仙台病毒 (SeV) 诱导的 IFN-β 产生，并且其转录激活结构域与这种抑制活性无关。此外，VP16 通过与 p65 相互作用，阻断 SeV 或肿瘤坏死因子 α 治疗诱导的 NF-κB 启动子的激活以及 NF-κB 依赖性基因的表达。共表达分析显示，VP16 选择性阻断 IFN 调节因子 3 (IRF-3) 介导的反式激活，但不能阻断 IRF-7 介导的反式激活。根据免疫共沉淀分析，VP16 在体内能够结合 IRF-3，但不能结合 IRF-7，但它不影响 IRF-3 二聚化、核易位或 DNA 结合活性。相反，VP16 与 CREB 结合蛋白 (CBP) 共激活剂相互作用，并在 HSV-1 感染的情况下有效抑制转录复合物 IRF-3-CBP 的形成。这些结果表明，VP16能够通过抑制NF-κB激活并干扰IRF-3来招募其共激活剂CBP来阻断IFN-β的产生，这对于导致HSV-1感染的早期事件可能很重要。
Host cells activate innate immune signaling pathways to defend against invading pathogens. To survive within an infected host, viruses have evolved intricate strategies to counteract host immune responses. Herpesviruses, including herpes simplex virus type 1 (HSV-1), have large genomes and therefore have the capacity to encode numerous proteins that modulate host innate immune responses. Here we define the contribution of HSV-1 tegument protein VP16 in the inhibition of beta interferon (IFN-β) production. VP16 was demonstrated to significantly inhibit Sendai virus (SeV)-induced IFN-β production, and its transcriptional activation domain was not responsible for this inhibition activity. Additionally, VP16 blocked the activation of the NF-κB promoter induced by SeV or tumor necrosis factor alpha treatment and expression of NF-κB-dependent genes through interaction with p65. Coexpression analysis revealed that VP16 selectively blocked IFN regulatory factor 3 (IRF-3)-mediated but not IRF-7-mediated transactivation. VP16 was able to bind to IRF-3 but not IRF-7in vivo, based on coimmunoprecipitation analysis, but it did not affect IRF-3 dimerization, nuclear translocation, or DNA binding activity. Rather, VP16 interacted with the CREB binding protein (CBP) coactivator and efficiently inhibited the formation of the transcriptional complexes IRF-3–CBP in the context of HSV-1 infection. These results illustrate that VP16 is able to block the production of IFN-β by inhibiting NF-κB activation and interfering with IRF-3 to recruit its coactivator CBP, which may be important to the early events leading to HSV-1 infection.