Date Published: March 22, 2019
Publisher: Public Library of Science
Author(s): Steven McFarlane, Anne Orr, Ashley P. E. Roberts, Kristen L. Conn, Victor Iliev, Colin Loney, Ana da Silva Filipe, Katherine Smollett, Quan Gu, Neil Robertson, Peter D. Adams, Taranjit Singh Rai, Chris Boutell, Robert F. Kalejta.
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.
The intrinsic, innate, and adaptive arms of host immunity cooperatively supress the replication and spread of invading viral pathogens. Conferred by constitutively expressed host factors, intrinsic immunity (also known as intrinsic antiviral resistance and cell autonomous immunity) restricts virus replication from the outset of infection [1–4]. By way of contrast, activation of Pattern Recognition Receptors (PRRs) by microbial specific Pathogen-Associated Molecular Patterns (PAMPs) leads to the induction of innate immune defences and the coordinated upregulation of a broad repertoire of host antiviral genes, principally cytokines (including interferons; IFNs) and interferon stimulated gene (ISG) products [3–6]. This induced immune response confers an enhanced antiviral state to limit virus spread and prime adaptive immune responses. Accordingly, many viruses have evolved counter measures to antagonize intrinsic and innate immune defences to promote the efficient onset of replication, propagation, and transmission to new hosts.
The replication-independent deposition of histone H3.3 into host chromatin has been predominantly linked to two histone chaperone complexes, namely Daxx/ATRX and HIRA/UBN1/CABIN1, which play important roles in the regulation of host chromatin structure, transcription, and DNA repair [86, 87]. The Daxx/ATRX complex typically mediates H3.3 deposition into cellular nucleosomes associated with telomeric and pericentric heterochromatin [88–92]; while the HIRA/UBN1/CABIN1 complex has been linked to the deposition of H3.3 into more transcriptionally accessible euchromatin and at sites of DNA damage [89, 93–96]. Recent reports have shown the HIRA H3.3 chaperone complex localizes at PML-NBs in response to infection with replication-defective herpesviruses to promote the assembly of viral genomes into chromatin for subsequent epigenetic silencing [17, 18]. However, the kinetics of HIRA recruitment to infecting viral genomes and PML-NBs under lytic replication conditions had yet to be examined. Here we report that HIRA displays spatiotemporally distinct kinetics of recruitment to infecting HSV-1 genomes and PML-NBs, which independently contribute to the regulation of intrinsic and innate immune defences in response to herpesvirus infection.