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

McFarlane, S. et al. (2019) The histone chaperone HIRA promotes the induction of host innate immune defences in response to HSV-1 infection. PLoS Pathogens, 15(3), e1007667. (doi: 10.1371/journal.ppat.1007667) (PMID:30901352) (PMCID:PMC6472835)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Gu, Dr Quan and Loney, Mr Colin and Rai, Dr Taranjit and Da Silva Filipe, Dr Ana and Roberts, Dr Ashley and Adams, Professor Peter and Orr, Mrs Anne and Boutell, Dr Chris and Smollett, Dr Katherine and Robertson, Neil and Conn, Dr Kristen and Iliev, Vic and McFarlane, Mr Steven
Creator Roles:
McFarlane, S.Data curation, Formal analysis, Investigation, Methodology
Orr, A.Data curation, Formal analysis, Investigation
Roberts, A. P.E.Data curation, Formal analysis, Investigation, Writing – review and editing
Conn, K. L.Investigation, Writing – original draft, Writing – review and editing
Iliev, V.Data curation
Iliev, V.Formal analysis, Investigation
Loney, C.Data curation, Formal analysis
da Silva Filipe, A.Methodology, Project administration
Smollett, K.Investigation
Gu, Q.Data curation
Robertson, N.Data curation, Formal analysis, Software
Adams, P. D.Resources
Rai, T. S.Data curation, Formal analysis, Investigation
Boutell, C.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing
Authors: McFarlane, S., Orr, A., Roberts, A. P.E., Conn, K. L., Iliev, V., Loney, C., da Silva Filipe, A., Smollett, K., Gu, Q., Robertson, N., Adams, P. D., Rai, T. S., and Boutell, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN (Online):1553-7374
Published Online:22 March 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in PLoS Pathogens 15(3):e1007667
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656521The role of ubiquitin and ubiquitin-like proteins during viral infectionChris BoutellMedical Research Council (MRC)MC_UU_12014/5MVLS III - CENTRE FOR VIRUS RESEARCH