Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response.
Novel Role for Protein Inhibitor of Activated STAT 4 (PIAS4) in the Restriction of Herpes Simplex Virus 1 by the Cellular Intrinsic Antiviral Immune Response.
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DOI：
10.1128/jvi.03055-15
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发表时间：
2016-05
影响因子：
5.4
通讯作者：
Boutell C
中科院分区：
文献类型：
--
作者：
Conn KL;Wasson P;McFarlane S;Tong L;Brown JR;Grant KG;Domingues P;Boutell C
小泛素样修饰物（SUMO）被内在抗病毒免疫反应用于限制病毒病原体，如单纯疱疹病毒1（HSV-1）。尽管依赖SUMO化发挥其抗病毒作用的宿主因子的表征，介导这些SUMO化事件的酶仍有待确定。我们发现，未结合的SUMO水平在很大程度上保持整个感染，无论存在的ICP 0，HSV-1 SUMO靶向泛素连接酶。此外，在不存在ICP 0的情况下，如果HSV-1 DNA不复制，则高分子量SUMO缀合蛋白不会积累。这些数据强调了SUMO信号在整个感染过程中的持续重要性。我们发现，SUMO连接酶蛋白抑制剂激活STAT 4（PIAS 4）是上调HSV-1感染期间，并定位到核域，包含病毒DNA。PIAS 4通过SUMO相互作用基序（SIM）依赖性机制被招募到与HSV-1基因组进入相关的位点，该机制被ICP 0破坏稳定。相反，PIAS 4通过SIM独立机制在复制区室中积累，而与ICP 0表达无关。PIAS 4的消耗增强了ICP 0无效突变体HSV-1的复制，其易受内在抗病毒免疫应答的限制。PIAS 4介导的限制机制与特征性内在抗病毒因子早幼粒细胞白血病蛋白的限制机制具有协同作用，并被ICP 0拮抗。我们提供了PIAS 4是一种内在抗病毒因子的第一个证据。PIAS 4在固有抗病毒免疫中的这种新作用与皮亚斯蛋白作为先天免疫抑制剂的已知作用形成对比。 小泛素样修饰蛋白（SUMO）的翻译后修饰调节宿主免疫和病毒复制的多个方面。SUMO连接酶的激活STAT（皮亚斯）家族的蛋白质抑制剂主要与先天免疫信号传导的抑制相关。我们现在确定了一个独特的和对比的作用，皮亚斯蛋白作为正调节剂的内在抗病毒免疫反应，单纯疱疹病毒1（HSV-1）感染。我们发现PIAS 4在整个感染过程中重新定位到含有病毒DNA的核结构域。PIAS 4单独或与内源性抗病毒因子早幼粒细胞白血病蛋白组合的耗竭显著损害对HSV-1感染的内源性抗病毒免疫应答。我们的数据揭示了PIAS 4在细胞介导的疱疹病毒限制中的新的和动态的作用，并建立了皮亚斯家族SUMO连接酶在DNA病毒感染的内在抗病毒免疫应答中的新的功能作用。
Small ubiquitin-like modifier (SUMO) is used by the intrinsic antiviral immune response to restrict viral pathogens, such as herpes simplex virus 1 (HSV-1). Despite characterization of the host factors that rely on SUMOylation to exert their antiviral effects, the enzymes that mediate these SUMOylation events remain to be defined. We show that unconjugated SUMO levels are largely maintained throughout infection regardless of the presence of ICP0, the HSV-1 SUMO-targeted ubiquitin ligase. Moreover, in the absence of ICP0, high-molecular-weight SUMO-conjugated proteins do not accumulate if HSV-1 DNA does not replicate. These data highlight the continued importance for SUMO signaling throughout infection. We show that the SUMO ligase protein inhibitor of activated STAT 4 (PIAS4) is upregulated during HSV-1 infection and localizes to nuclear domains that contain viral DNA. PIAS4 is recruited to sites associated with HSV-1 genome entry through SUMO interaction motif (SIM)-dependent mechanisms that are destabilized by ICP0. In contrast, PIAS4 accumulates in replication compartments through SIM-independent mechanisms irrespective of ICP0 expression. Depletion of PIAS4 enhances the replication of ICP0-null mutant HSV-1, which is susceptible to restriction by the intrinsic antiviral immune response. The mechanisms of PIAS4-mediated restriction are synergistic with the restriction mechanisms of a characterized intrinsic antiviral factor, promyelocytic leukemia protein, and are antagonized by ICP0. We provide the first evidence that PIAS4 is an intrinsic antiviral factor. This novel role for PIAS4 in intrinsic antiviral immunity contrasts with the known roles of PIAS proteins as suppressors of innate immunity. IMPORTANCE Posttranslational modifications with small ubiquitin-like modifier (SUMO) proteins regulate multiple aspects of host immunity and viral replication. The protein inhibitor of activated STAT (PIAS) family of SUMO ligases is predominantly associated with the suppression of innate immune signaling. We now identify a unique and contrasting role for PIAS proteins as positive regulators of the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1) infection. We show that PIAS4 relocalizes to nuclear domains that contain viral DNA throughout infection. Depletion of PIAS4, either alone or in combination with the intrinsic antiviral factor promyelocytic leukemia protein, significantly impairs the intrinsic antiviral immune response to HSV-1 infection. Our data reveal a novel and dynamic role for PIAS4 in the cellular-mediated restriction of herpesviruses and establish a new functional role for the PIAS family of SUMO ligases in the intrinsic antiviral immune response to DNA virus infection.