title: The Epstein-Barr Virus Immunoevasins BCRF1 and BPLF1 Are Expressed by a Mechanism Independent of the Canonical Late Pre-initiation Complex.
abstract: Subversion of host immune surveillance is a crucial step in viral pathogenesis. Epstein-Barr virus (EBV) encodes two immune evasion gene products, BCRF1 (viral IL-10) and BPLF1 (deubiquitinase/deneddylase); both proteins suppress antiviral immune responses during primary infection. The BCRF1 and BPLF1 genes are expressed during the late phase of the lytic cycle, an essential but poorly understood phase of viral gene expression. Several late gene regulators recently identified in beta and gamma herpesviruses form a viral pre-initiation complex for transcription. Whether each of these late gene regulators is necessary for transcription of all late genes is not known. Here, studying viral gene expression in the absence and presence of siRNAs to individual components of the viral pre-initiation complex, we identified two distinct groups of late genes. One group includes late genes encoding the two immunoevasins, BCRF1 and BPLF1, and is transcribed independently of the viral pre-initiation complex. The second group primarily encodes viral structural proteins and is dependent on the viral pre-initiation complex. The protein kinase BGLF4 is the only known late gene regulator necessary for expression of both groups of late genes. ChIP-seq analysis showed that the transcription activator Rta associates with the promoters of eight late genes including genes encoding the viral immunoevasins. Our results demonstrate that late genes encoding immunomodulatory proteins are transcribed by a mechanism distinct from late genes encoding viral structural proteins. Understanding the mechanisms that specifically regulate expression of the late immunomodulatory proteins could aid the development of antiviral drugs that impair immune evasion by the oncogenic EB virus.
authors.affiliation: Department of Pediatrics Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: McKenzie
authors.affiliation: Yale Center for Genome Analysis (YCGA), Yale University, West Haven, Connecticut, United States of America.
authors.forename: Francesc
authors.identifier: http://orcid.org/0000-0001-7476-9822
authors.initials: F
authors.lastname: Lopez-Giraldez
authors.affiliation: Department of Tumor Virology, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg, Germany.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.affiliation: Department of Pediatrics Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Ann
authors.identifier: http://orcid.org/0000-0003-3183-510X
authors.initials: A
authors.lastname: Walsh
authors.affiliation: Department of Pediatrics Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Guindy
mesh_terms: D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D057131:Immune Evasion / Q000235:genetics* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins / Q000096:biosynthesis* / Q000235:genetics; D015678:Viral Structural Proteins / Q000096:biosynthesis
chemical_list: C066460:BCRF1 protein, Human herpesvirus 4; C495488:BPLF1 protein, Epstein-Barr virus; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D015678:Viral Structural Proteins