SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1.
SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1.
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DOI：
10.1128/jvi.00426-16
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发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Boutell C
中科院分区：
文献类型：
--
作者：
Brown JR;Conn KL;Wasson P;Charman M;Tong L;Grant K;McFarlane S;Boutell C
内源性抗病毒免疫的各个方面由早幼粒细胞白血病核体（PML-NB）组成蛋白介导。在疱疹病毒感染期间，这些抗病毒蛋白独立地募集到包含感染病毒基因组的核结构域，以协同促进病毒基因组沉默。执行这种特定的抗病毒反应的中心是小泛素样修饰物（SUMO）信号通路。然而，参与SUMO化的酶没有完全表征。我们确定SUMO连接酶蛋白抑制剂激活的STAT 1（PIAS 1）作为PML-NB蛋白的组成部分。我们发现PIAS 1以SUMO相互作用基序（SIM）依赖的方式定位于PML-NB，这需要SUMO化或SUMO化能力的PML。感染单纯疱疹病毒1（HSV-1）后，PIAS 1以SIM依赖性方式募集到与病毒基因组进入相关的核位点，这与其他充分表征的PML-NB蛋白的SIM依赖性募集机制一致。然而，与Daxx和Sp100相反，PML增强了PIAS 1的募集。PIAS 1促进SUMO 1在与HSV-1基因组进入相关的核位点的稳定积累，而其他评价的PML-NB蛋白的积累独立于PIAS 1发生。我们表明，PIAS 1合作有助于HSV-1的限制，通过这些机制是添加剂的PML和合作与PIAS 4。PIAS 1的抗病毒机制被ICP 0抵消，ICP 0是HSV-1 SUMO靶向泛素连接酶，其通过不直接导致PIAS 1降解的机制破坏PIAS 1向包含感染HSV-1基因组的核结构域的募集。 适应性免疫、先天免疫和内在免疫相互配合，有效地限制病毒病原体的繁殖。由组成型表达的细胞蛋白介导的固有免疫代表了细胞内抵抗感染的第一道防线。PML-NB组成蛋白介导限制单纯疱疹病毒1（HSV-1）以及其他病毒的固有免疫方面。这些蛋白质通过依赖于SUMO信号传导的机制抑制病毒复制。然而，参与SUMO化的酶是未知的。我们确定SUMO连接酶PIAS 1作为PML-NB抗病毒蛋白的组成部分。这一发现区分了SUMO连接酶，其可能介导PML-NB介导的内在免疫中重要的信号传导事件。此外，这项研究补充了PIAS 4作为内在抗病毒因子的最新鉴定，支持皮亚斯蛋白作为宿主对病毒感染的免疫的正调节剂和负调节剂的作用。
Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukemia nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signaling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase protein inhibitor of activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation-competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well-characterized PML-NB proteins. In contrast to that of Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation. IMPORTANCE Adaptive, innate, and intrinsic immunity cooperatively and efficiently restrict the propagation of viral pathogens. Intrinsic immunity mediated by constitutively expressed cellular proteins represents the first line of intracellular defense against infection. PML-NB constituent proteins mediate aspects of intrinsic immunity to restrict herpes simplex virus 1 (HSV-1) as well as other viruses. These proteins repress viral replication through mechanisms that rely on SUMO signaling. However, the participating SUMOylation enzymes are not known. We identify the SUMO ligase PIAS1 as a constituent PML-NB antiviral protein. This finding distinguishes a SUMO ligase that may mediate signaling events important in PML-NB-mediated intrinsic immunity. Moreover, this research complements the recent identification of PIAS4 as an intrinsic antiviral factor, supporting a role for PIAS proteins as both positive and negative regulators of host immunity to virus infection.