title: Functional interaction between JC virus late regulatory agnoprotein and cellular Y-box binding transcription factor, YB-1.
abstract: Human polyomavirus JC virus (JCV) is a causative agent of progressive multifocal leukoencephalopathy which results from lytic infection of glial cells. Although significant progress has been made in understanding the regulation of JCV gene transcription, the mechanism(s) underlying the viral lytic cycle remains largely unknown. We recently reported that the JCV late auxiliary Agnoprotein may have a regulatory role in JCV gene transcription and replication. Here, we investigated its regulatory function in viral gene transcription through its physical and functional interaction with YB-1, a cellular transcription factor which contributes to JCV gene expression in glial cells. Time course studies revealed that Agnoprotein is first detected at day 3 postinfection and that its level increased during the late stage of the infection cycle. Agnoprotein is mainly localized to the cytoplasmic compartment of the infected cell, with high concentrations found in the perinuclear region. While the position of Agnoprotein throughout the infection cycle remained relatively unaltered, the subcellular distribution of YB-1 between the cytoplasm and nucleus changed. Results from coimmunoprecipitation and glutathione S-transferase pull-down experiments revealed that Agnoprotein physically interacts with YB-1 and that the amino-terminal region of Agnoprotein, between residues 1 and 36, is critical for this association. Further investigation of this interaction by functional assays demonstrated that Agnoprotein negatively regulates YB-1-mediated gene transcription and that the region corresponding to residues 1 to 36 of Agnoprotein is important for the observed regulatory event. Taken together, these data demonstrate that the interaction of the viral late regulatory Agnoprotein and cellular Y-box binding factor YB-1 modulates transcriptional activity of JCV promoters.
authors.affiliation: Laboratory of Molecular Neurovirology, Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Safak
authors.forename: Beata
authors.initials: B
authors.lastname: Sadowska
authors.forename: Robert
authors.initials: R
authors.lastname: Barrucco
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015967:Gene Expression Regulation, Viral; D005909:Glioblastoma; D006801:Humans; D007577:JC Virus / Q000472:pathogenicity* / Q000502:physiology; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D027601:Polyomavirus Infections / Q000821:virology; D011401:Promoter Regions, Genetic; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D051840:Y-Box-Binding Protein 1; D000086082:Viroporin Proteins
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C042559:agnoprotein, polyomavirus; D000086082:Viroporin Proteins