MRC-University of Glasgow Centre for Virus Research (CVR), Garscube Campus, Glasgow, Scotland, United Kingdom.
Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatoon, CA.
PLoS Pathog. 2019 Mar 22;15(3):e1007667. doi: 10.1371/journal.ppat.1007667. eCollection 2019 Mar.
Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
宿主固有免疫防御在限制入侵病毒病原体的细胞内繁殖和发病机制方面发挥着关键作用。在这里，我们表明组蛋白 H3.3 伴侣 HIRA（组蛋白细胞周期调节剂）与早幼粒细胞白血病核体（PML-NBs）结合，刺激诱导针对单纯疱疹病毒 1（HSV-1）感染的固有免疫防御。在固有免疫信号激活后，HIRA 以依赖 Janus 相关激酶（JAK）、细胞周期蛋白依赖性激酶（CDK）和 Sp100 的方式定位于 PML-NBs。RNA-seq 分析显示，HIRA 促进了广泛的宿主基因的转录上调，这些基因调节了对 HSV-1 感染的固有免疫，包括参与 MHC-I 抗原呈递、细胞因子信号和干扰素刺激基因（ISG）表达的基因。ChIP-seq 分析显示，PML-NBs 的主要支架蛋白 PML 是 HIRA 富集到 ISGs 所必需的，这确定了 PML 在 HIRA 依赖的病毒感染固有免疫调节中的作用。我们的数据确定了 HIRA 在病毒基因表达的固有沉默和诱导固有免疫防御以分别限制 HSV-1 感染的起始和传播中的独立作用。这些细胞内宿主防御被 HSV-1 泛素连接酶 ICP0 拮抗，后者破坏了 HIRA 在感染病毒基因组和 PML-NBs 上的稳定募集，在感染的时空不同阶段。我们的研究强调了组蛋白伴侣在调节病毒感染细胞内免疫的多个阶段的重要性，这些发现很可能在许多临床上重要的病毒病原体的细胞限制中具有高度相关性。
