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

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

    Research output: Contribution to journalArticle

    Abstract

    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.

    LanguageEnglish
    Article numbere1007667
    JournalPLoS Pathogens
    Volume15
    Issue number3
    DOIs
    Publication statusPublished - 1 Mar 2019

    Fingerprint

    Histone Chaperones
    Human Herpesvirus 1
    Virus Diseases
    Leukemia
    Innate Immunity
    Histones
    Janus Kinases
    Gene Expression
    Viral Genes
    Cyclin-Dependent Kinases
    Viral Genome
    Antigen Presentation
    Ligases
    Ubiquitin
    Interferons
    Immunity
    Cell Cycle
    Up-Regulation
    RNA
    Cytokines

    Cite this

    McFarlane, S., Orr, A., Roberts, A. P. E., Conn, K. L., Iliev, V., Loney, C., ... Boutell, C. (2019). The histone chaperone hira promotes the induction of host innate immune defences in response to HSV-1 infection. PLoS Pathogens, 15(3), [e1007667]. https://doi.org/10.1371/journal.ppat.1007667
    McFarlane, Steven ; Orr, Anne ; Roberts, Ashley P.E. ; Conn, Kristen L. ; Iliev, Victor ; Loney, Colin ; Filipe, Ana Da Silva ; Smollett, Katherine ; Gu, Quan ; Robertson, Neil ; Adams, Peter D. ; Rai, Taranjit Singh ; Boutell, Chris. / The histone chaperone hira promotes the induction of host innate immune defences in response to HSV-1 infection. In: PLoS Pathogens. 2019 ; Vol. 15, No. 3.
    @article{d29c4c955b6942b5929bb915630f292d,
    title = "The histone chaperone hira promotes the induction of host innate immune defences in response to HSV-1 infection",
    abstract = "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 = "Steven McFarlane and Anne Orr and Roberts, {Ashley P.E.} and Conn, {Kristen L.} and Victor Iliev and Colin Loney and Filipe, {Ana Da Silva} and Katherine Smollett and Quan Gu and Neil Robertson and Adams, {Peter D.} and Rai, {Taranjit Singh} and Chris Boutell",
    year = "2019",
    month = "3",
    day = "1",
    doi = "10.1371/journal.ppat.1007667",
    language = "English",
    volume = "15",
    journal = "PLoS Pathogens",
    issn = "1553-7366",
    number = "3",

    }

    McFarlane, S, Orr, A, Roberts, APE, Conn, KL, Iliev, V, Loney, C, Filipe, ADS, Smollett, K, Gu, Q, Robertson, N, Adams, PD, Rai, TS & Boutell, C 2019, 'The histone chaperone hira promotes the induction of host innate immune defences in response to HSV-1 infection', PLoS Pathogens, vol. 15, no. 3, e1007667. https://doi.org/10.1371/journal.ppat.1007667

    The histone chaperone hira promotes the induction of host innate immune defences in response to HSV-1 infection. / McFarlane, Steven; Orr, Anne; Roberts, Ashley P.E.; Conn, Kristen L.; Iliev, Victor; Loney, Colin; Filipe, Ana Da Silva; Smollett, Katherine; Gu, Quan; Robertson, Neil; Adams, Peter D.; Rai, Taranjit Singh; Boutell, Chris.

    In: PLoS Pathogens, Vol. 15, No. 3, e1007667, 01.03.2019.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The histone chaperone hira promotes the induction of host innate immune defences in response to HSV-1 infection

    AU - McFarlane, Steven

    AU - Orr, Anne

    AU - Roberts, Ashley P.E.

    AU - Conn, Kristen L.

    AU - Iliev, Victor

    AU - Loney, Colin

    AU - Filipe, Ana Da Silva

    AU - Smollett, Katherine

    AU - Gu, Quan

    AU - Robertson, Neil

    AU - Adams, Peter D.

    AU - Rai, Taranjit Singh

    AU - Boutell, Chris

    PY - 2019/3/1

    Y1 - 2019/3/1

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=85065051205&partnerID=8YFLogxK

    U2 - 10.1371/journal.ppat.1007667

    DO - 10.1371/journal.ppat.1007667

    M3 - Article

    VL - 15

    JO - PLoS Pathogens

    T2 - PLoS Pathogens

    JF - PLoS Pathogens

    SN - 1553-7366

    IS - 3

    M1 - e1007667

    ER -