title: X-box-binding protein 1 activates lytic Epstein-Barr virus gene expression in combination with protein kinase D.
abstract: Epstein-Barr virus (EBV) establishes a latent form of infection in memory B cells, while antibody-secreting plasma cells often harbor the lytic form of infection. The switch between latent and lytic EBV infection is mediated by the two viral immediate-early proteins BZLF1 (Z) and BRLF1 (R), which are not expressed in latently infected B cells. Here we demonstrate that a cellular transcription factor that plays an essential role in plasma cell differentiation, X-box-binding protein 1 (XBP-1), also activates the transcription of the two EBV immediate-early gene promoters. In reporter gene assays, XBP-1 alone was sufficient to activate the R promoter, whereas the combination of XBP-1 and protein kinase D (PKD) was required for efficient activation of the Z promoter. Most importantly, the expression of XBP-1 and activated PKD was sufficient to induce lytic viral gene expression in EBV-positive nasopharyngeal carcinoma cells and lymphoblastoid cells, while an XBP-1 small interfering RNA inhibited constitutive lytic EBV gene expression in lymphoblastoid cells. These results suggest that the plasma cell differentiation factor XBP-1, in combination with activated PKD, can mediate the reactivation of EBV, thereby allowing the viral life cycle to be intimately linked to plasma cell differentiation.
authors.affiliation: Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Prasanna M
authors.initials: PM
authors.lastname: Bhende
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dickerson
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Feng
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Kenney
mesh_terms: D001483:Base Sequence; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014635:Valproic Acid / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency; D000071717:X-Box Binding Protein 1
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D014635:Valproic Acid; C089212:protein kinase D; D011493:Protein Kinase C; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases