The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection
The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection
复制标题
DOI：
10.1371/journal.ppat.1007667
复制
发表时间：
2019-03-01
期刊：
影响因子：
6.7
通讯作者：
Boutell, Chris
中科院分区：
文献类型：
--
作者：
McFarlane, Steven;Orr, Anne;Boutell, Chris
宿主先天免疫防御在限制病毒病原体入侵的细胞内繁殖和发病机制中起着至关重要的作用。本研究表明，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小体（PML-NBs）相关，可刺激诱导对单纯疱疹病毒1型（HSV-1）感染的先天免疫防御。在先天免疫信号激活后，HIRA以Janus-Associated Kinase （JAK）、Cyclin Dependent Kinase （CDK）和sp100依赖的方式定位于PML-NBs。RNA-seq分析显示，HIRA促进了一系列宿主基因的转录上调，这些基因调节了对HSV-1感染的先天免疫，包括那些与mhc -1抗原呈递、细胞因子信号传导和干扰素刺激基因（ISG）表达有关的基因。ChIP-seq分析显示PML是PML- nbs的主要支架蛋白，是HIRA在isg上富集所必需的，这表明PML在HIRA依赖性的病毒感染先天免疫调节中起作用。我们的数据分别确定了HIRA在病毒基因表达的内在沉默和诱导先天免疫防御以限制HSV-1感染的发生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，这破坏了HIRA在感染病毒基因组和PML-NBs的时空不同阶段的稳定募集。我们的研究强调了组蛋白伴侣在调节病毒感染的细胞内免疫的多个阶段的重要性，这些发现可能与许多临床重要的病毒病原体的细胞限制高度相关。宿主先天免疫防御在细胞限制入侵的病毒病原体和刺激适应性免疫应答中起着至关重要的作用。宿主免疫调控的一个关键组成部分是快速诱导细胞因子信号传导和干扰素刺激基因产物（ISGs）的表达，这赋予了一种难以抑制的抗病毒状态，以限制病毒的传播和发病机制。虽然激活先天免疫防御的信号转导级联已经很好地建立起来，但对于加速这种广泛的抗病毒宿主基因表达以应对病原体入侵的细胞宿主因子知之甚少。在这里，我们发现HIRA，一种组蛋白H3.3伴侣，与PML-NBs结合，刺激对HSV-1感染的先天免疫防御的诱导。我们的研究强调了组蛋白伴侣在协调调节宿主免疫应答病原体入侵的多个阶段中的重要性，并确定了HIRA在诱导病毒感染的先天免疫中的关键作用。
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.Author summary Host innate immune defences play critical roles in the cellular restriction of invading viral pathogens and the stimulation of adaptive immune responses. A key component in the regulation of this arm of host immunity is the rapid induction of cytokine signalling and the expression of interferon stimulated gene products (ISGs), which confer a refractory antiviral state to limit virus propagation and pathogenesis. While the signal transduction cascades that activate innate immune defences are well established, little is known about the cellular host factors that expedite the expression of this broad repertoire of antiviral host genes in response to pathogen invasion. Here we show that HIRA, a histone H3.3 chaperone, associates with PML-NBs to stimulate the induction of innate immune defences in response to HSV-1 infection. Our study highlights the importance of histone chaperones in the coordinated regulation of multiple phases of host immunity in response to pathogen invasion and identifies a key role for HIRA in the induction of innate immunity to virus infection.