The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection

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.