Epstein-Barr virus nuclear antigen 2 trans-activates the cellular antiapoptotic bfl-1 gene by a CBF1/RBPJ kappa-dependent pathway.
The human herpesvirus Epstein-Barr virus (EBV) establishes latency and promotes the long-term survival of its host B cell by targeting the molecular machinery controlling cell fate decisions. The cellular antiapoptotic bfl-1 gene confers protection from apoptosis under conditions of growth factor deprivation when expressed ectopically in an EBV-negative Burkitt's lymphoma-derived cell line (B. D'Souza, M. Rowe, and D. Walls, J. Virol. 74:6652-6658, 2000), and the EBV latent membrane protein 1 (LMP1) and its cellular functional homologue CD40 can both drive bfl-1 via an NF-kappaB-dependent enhancer element in the bfl-1 promoter (B. N. D'Souza, L. C. Edelstein, P. M. Pegman, S. M. Smith, S. T. Loughran, A. Clarke, A. Mehl, M. Rowe, C. Gélinas, and D. Walls, J. Virol. 78:1800-1816, 2004). Here we show that the EBV nuclear antigen 2 (EBNA2) also upregulates bfl-1. EBNA2 trans-activation of bfl-1 requires CBF1 (or RBP-J kappa), a nuclear component of the Notch signaling pathway, and there is an essential role for a core consensus CBF1-binding site on the bfl-1 promoter. trans-activation is dependent on the EBNA2-CBF1 interaction, is modulated by other EBV gene products known to interact with the CBF1 corepressor complex, and does not involve activation of NF-kappaB. bfl-1 expression is induced and maintained at high levels by the EBV growth program in a lymphoblastoid cell line, and withdrawal of either EBNA2 or LMP1 does not lead to a reduction in bfl-1 mRNA levels in this context, whereas the simultaneous loss of both EBV proteins results in a major decrease in bfl-1 expression. These findings are relevant to our understanding of EBV persistence, its role in malignant disease, and the B-cell developmental process.
Pegman
Pamela M
PM
School of Biotechnology and National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland.
Smith
Sinéad M
SM
D'Souza
Brendan N
BN
Loughran
Sinéad T
ST
Maier
Sabine
S
Kempkes
Bettina
B
Cahill
Paul A
PA
Simmons
Matthew J
MJ
Gélinas
Céline
C
Walls
Dermot
D
D000956:Antigens, Viral / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000821:virology; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000254:growth & development*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins
D000956:Antigens, Viral; C096816:BCL2-related protein A1; C402641:EBNA-2 protein, Human herpesvirus 4; C508151:EBNA-3A antigen; C422762:EBNA-3B antigen; C498774:EBNA-3C, epstein-barr virus; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; C497570:RBPJ protein, human; D012333:RNA, Messenger; D051880:Receptors, Notch; D012097:Repressor Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins