title: Repression of the proapoptotic cellular BIK/NBK gene by Epstein-Barr virus antagonizes transforming growth factor β1-induced B-cell apoptosis.
abstract: The Epstein-Barr virus (EBV) establishes a lifelong latent infection in humans. EBV infection of primary B cells causes cell activation and proliferation, a process driven by the viral latency III gene expression program, which includes EBV nuclear proteins (EBNAs), latent membrane proteins, and untranslated RNAs, including microRNAs. Some latently infected cells enter the long-lived memory B-cell compartment and express only EBNA1 transiently (Lat I) or no EBV protein at all (Lat 0). Targeting the molecular machinery that controls B-cell fate decisions, including the Bcl-2 family of apoptosis-regulating proteins, is crucial to the EBV cycle of infection. Here, we show that BIK (also known as NBK), which encodes a proapoptotic "sensitizer" protein, is repressed by the EBNA2-driven Lat III program but not the Lat I program. BIK repression occurred soon after infection of primary B cells by EBV but not by a recombinant EBV in which the EBNA2 gene had been knocked out. Ectopic BIK induced apoptosis in Lat III cells by a mechanism dependent on its BH3 domain and the activation of caspases. We show that EBNA2 represses BIK in EBV-negative B-cell lymphoma-derived cell lines and that this host-virus interaction can inhibit the proapoptotic effect of transforming growth factor β1 (TGF-β1), a key physiological mediator of B-cell homeostasis. Reduced levels of TGF-β1-associated regulatory SMAD proteins were bound to the BIK promoter in response to EBV Lat III or ectopic EBNA2. These data are evidence of an additional mechanism used by EBV to promote B-cell survival, namely, the transcriptional repression of the BH3-only sensitizer BIK.
  
  
  OBJECTIVE
  Over 90% of adult humans are infected with the Epstein-Barr virus (EBV). EBV establishes a lifelong silent infection, with its DNA residing in small numbers of blood B cells that are a reservoir from which low-level virus reactivation and shedding in saliva intermittently occur. Importantly, EBV DNA is found in some B-cell-derived tumors in which viral genes play a key role in tumor cell emergence and progression. Here, we report for the first time that EBV can shut off a B-cell gene called BIK. When activated by a molecular signal called transforming growth factor β1 (TGF-β1), BIK plays an important role in killing unwanted B cells, including those infected by viruses. We describe the key EBV-B-cell molecular interactions that lead to BIK shutoff. These findings further our knowledge of how EBV prevents the death of its host cell during infection. They are also relevant to certain posttransplant lymphomas where unregulated cell growth is caused by EBV genes.
authors.affiliation: School of Biotechnology and National Centre for Sensor Research, Dublin City University, Dublin, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Campion
authors.forename: Roya
authors.initials: R
authors.lastname: Hakimjavadi
authors.forename: Sinéad T
authors.initials: ST
authors.lastname: Loughran
authors.forename: Susan
authors.initials: S
authors.lastname: Phelan
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Smith
authors.forename: Brendan N
authors.initials: BN
authors.lastname: D'Souza
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Tierney
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Bell
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cahill
authors.forename: Dermot
authors.initials: D
authors.lastname: Walls
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000821:virology*; D002460:Cell Line; D015536:Down-Regulation; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C402641:EBNA-2 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D053773:Transforming Growth Factor beta1; D014764:Viral Proteins