title: EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription.
abstract: Productive infection by herpesviruses involve the disabling of host-cell intrinsic defenses by viral encoded tegument proteins. Epstein-Barr Virus (EBV) typically establishes a non-productive, latent infection and it remains unclear how it confronts the host-cell intrinsic defenses that restrict viral gene expression. Here, we show that the EBV major tegument protein BNRF1 targets host-cell intrinsic defense proteins and promotes viral early gene activation. Specifically, we demonstrate that BNRF1 interacts with the host nuclear protein Daxx at PML nuclear bodies (PML-NBs) and disrupts the formation of the Daxx-ATRX chromatin remodeling complex. We mapped the Daxx interaction domain on BNRF1, and show that this domain is important for supporting EBV primary infection. Through reverse transcription PCR and infection assays, we show that BNRF1 supports viral gene expression upon early infection, and that this function is dependent on the Daxx-interaction domain. Lastly, we show that knockdown of Daxx and ATRX induces reactivation of EBV from latently infected lymphoblastoid cell lines (LCLs), suggesting that Daxx and ATRX play a role in the regulation of viral chromatin. Taken together, our data demonstrate an important role of BNRF1 in supporting EBV early infection by interacting with Daxx and ATRX; and suggest that tegument disruption of PML-NB-associated antiviral resistances is a universal requirement for herpesvirus infection in the nucleus.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tsai
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Thikmyanova
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wojcechowskyj
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency; D000075924:X-linked Nuclear Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C062724:P140 protein, Epstein-barr virus; D034741:RNA, Small Interfering; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
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