title: The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC.
abstract: Brd4 is an epigenetic reader protein and a member of the BET (bromodomain and extra terminal domain) family of proteins with two bromodomains that recognize acetylated lysine residues. Brd4 specifically binds to acetylated transcription factor NF-κB p65 and coactivates transcription. Polyomavirus JC (JCV) is regulated by a noncoding control region (NCCR) containing promoter/enhancer elements for viral gene expression including a binding site for NF-κB, which responds to proinflammatory cytokines such as TNF-α, the DNA damage response, calcium signaling and acetylation of the NF-κB p65 subunit on lysine residues K218 and K221. Earlier studies indicated that NF-κB is involved in the reactivation of persistent/latent JCV in glial cells to cause progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the brain caused by replication of JCV in glial cells. To investigate the mechanism of action of NF-κB acetylation on JCV transcription, we examined Brd4 and found that JCV early transcription was stimulated by Brd4 via the JCV NF-κB site and that p65 K218 and K221 were involved. Treatment with the Brd4 inhibitor JQ1(+) or mutation of either K218 or K221 to glutamine (K218R or K221) inhibited this stimulation and decreased the proportion of p65 in the nucleus. We conclude that Brd4 is involved in the regulation of the activation status of JCV in glial cells.
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Hassen S
authors.initials: HS
authors.lastname: Wollebo
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bellizzi
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Dominique H
authors.initials: DH
authors.lastname: Cossari
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Julian
authors.initials: J
authors.lastname: Salkind
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Safak
authors.affiliation: Center for Neurovirology, Department of Neuroscience, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA. martyn.white@temple.edu.
authors.forename: Martyn K
authors.initials: MK
authors.lastname: White
mesh_terms: D000107:Acetylation; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D017930:Genes, Reporter; D054884:Host-Pathogen Interactions; D006801:Humans; D007577:JC Virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D014775:Virus Activation; D014779:Virus Replication / Q000187:drug effects*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D008156:Luciferases; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Epigenetic regulation; JC virus; Progressive multifocal leukoencephalopathy; Protein acetylation; Viral persistence; Viral reactivation