Repression of the Proapoptotic Cellular BIK/NBK Gene by Epstein-Barr Virus Antagonizes Transforming Growth Factor β1-Induced B-Cell Apoptosis

被引:19
作者
Campion, Eva M. [1 ,2 ]
Hakimjavadi, Roya [1 ,2 ]
Loughran, Sinead T. [1 ,2 ]
Phelan, Susan [1 ,2 ]
Smith, Sinead M. [1 ,2 ]
D'Souza, Brendan N. [1 ,2 ]
Tierney, Rosemary J. [3 ]
Bell, Andrew I. [3 ]
Cahill, Paul A. [1 ,2 ,4 ]
Walls, Dermot [1 ,2 ]
机构
[1] Dublin City Univ, Sch Biotechnol, Dublin 9, Ireland
[2] Dublin City Univ, Natl Ctr Sensor Res, Dublin 9, Ireland
[3] Univ Birmingham, Coll Med & Dent Sci, Sch Canc Sci, Birmingham, W Midlands, England
[4] Dublin City Univ, Sch Biotechnol, Vasc Biol Res Grp, Dublin 9, Ireland
关键词
ANTIAPOPTOTIC BFL-1 GENE; BURKITTS-LYMPHOMA CELLS; BETA-MEDIATED APOPTOSIS; PROTOONCOGENE C-MYC; BREAST-CANCER CELLS; BCL-X-L; NUCLEAR ANTIGEN-2; ENDOPLASMIC-RETICULUM; LATENT MEMBRANE-PROTEIN-1; INFECTIOUS-MONONUCLEOSIS;
D O I
10.1128/JVI.03642-13
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 asNBK), 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. Weshow 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 beta 1 (TGF-beta 1), a key physiological mediator of B-cell homeostasis. Reduced levels of TGF-beta 1-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.
引用
收藏
页码:5001 / 5013
页数:13
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