Abstract
The HIRA histone chaperone complex deposits histone H3.3 into nucleosomes in a DNA replication- and sequence-independent manner. As herpesvirus genomes enter the nucleus as naked DNA, we asked whether the HIRA chaperone complex affects herpesvirus infection. After infection of primary cells with HSV or CMV, or transient transfection with naked plasmid DNA, HIRA re-localizes to PML bodies, sites of cellular anti-viral activity. HIRA co-localizes with viral genomes, binds to incoming viral and plasmid DNAs and deposits histone H3.3 onto these. Anti-viral interferons (IFN) specifically induce HIRA/PML co-localization at PML nuclear bodies and HIRA recruitment to IFN target genes, although HIRA is not required for IFN-inducible expression of these genes. HIRA is, however, required for suppression of viral gene expression, virus replication and lytic infection and restricts murine CMV replication in vivo. We propose that the HIRA chaperone complex represses incoming naked viral DNAs through chromatinization as part of intrinsic cellular immunity.
Highlights
The HIRA chaperone complex, comprised of HIRA/U BN1/CABIN1, collaborates with histone binding protein ASF1a to incorporate H3.3 into chromatin in a DNA replication-independent manner [1,2,3]
To prevent viral proteins from counteracting the cellular anti-viral response, cells were infected with UV-inactivated WT human cytomegalovirus strain AD169 (UVHCMV) or an HSV type 1 strain expressing a lacZ marker gene and harboring mutations in the viral transactivator proteins ICP0, ICP4 and VP16 which normally counteract cellular repressors
We demonstrate that the HIRA histone chaperone complex is involved in chromatinization of incoming viral DNAs and participates in cellular anti-viral intrinsic immunity
Summary
The HIRA chaperone complex, comprised of HIRA/U BN1/CABIN1, collaborates with histone binding protein ASF1a to incorporate H3.3 into chromatin in a DNA replication-independent manner [1,2,3]. The HIRA complex is targeted non- to naked DNA and so is thought to deposit histone H3.3 through a so-called ‘gap-filling’ function [4]. HIRA-mediated H3.3 deposition contributes to diverse biological functions. The HIRA protein is required for deposition of histone H3.3 at dynamic chromatin of active and poised genes and enhancers, polycomb target genes and sites of DNA damage repair [4,5,6,7,8]. HIRA’s role in H3.3 deposition is thought to underpin diverse physiological functions in metazoans, including sperm nucleus decondensation after fertilization [3], embryo development [5,14,15] and cell senescence and tumor suppression [16,17]
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