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Journal of Virology, February 2004, p. 1800-1816, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1800-1816.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Nuclear Factor {kappa}B-Dependent Activation of the Antiapoptotic bfl-1 Gene by the Epstein-Barr Virus Latent Membrane Protein 1 and Activated CD40 Receptor

Brendan N. D'Souza,1,{dagger} Leonard C. Edelstein,2,{ddagger} Pamela M. Pegman,1 Sinéad M. Smith,1 Sinéad T. Loughran,1 Ann Clarke,1,§ Anja Mehl,3,|| Martin Rowe,3 Céline Gélinas,2 and Dermot Walls1*

School of Biotechnology and National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland,1 Department of Biochemistry, Centre for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,2 Section of Infection and Immunity, University of Wales College of Medicine, Cardiff CF14 4XX, United Kingdom3

Received 20 August 2003/ Accepted 16 October 2003

Suppression of the cellular apoptotic program by the oncogenic herpesvirus Epstein-Barr virus (EBV) is central to both the establishment of latent infection and the development of EBV-associated malignancies. We have previously shown that expression of the EBV latent membrane protein 1 (LMP1) in Burkitt's lymphoma cell lines leads to increased mRNA levels from the cellular antiapoptotic bfl-1 gene (also known as A1). Furthermore, ectopic expression of Bfl-1 in an EBV-positive cell line exhibiting a latency type 1 infection protects against apoptosis induced by growth factor deprivation (B. N. D'Souza, M. Rowe, and D. Walls, J. Virol. 74:6652-6658, 2000). We now report that LMP1 drives bfl-1 promoter activity through interactions with components of the tumor necrosis factor receptor (TNFR)/CD40 signaling pathway. We present evidence that this process is NF-{kappa}B dependent, involves the recruitment of TNFR-associated factor 2, and is mediated to a greater extent by the carboxyl-terminal activating region 2 (CTAR2) relative to the CTAR1 domain of LMP1. Activation of CD40 receptor also led to increased bfl-1 mRNA levels and an NF-{kappa}B-dependent increase in bfl-1 promoter activity in Burkitt's lymphoma-derived cell lines. We have delineated a 95-bp region of the promoter that functions as an LMP1-dependent transcriptional enhancer in this cellular context. This sequence contains a novel NF-{kappa}B-like binding motif that is essential for transactivation of bfl-1 by LMP1, CD40, and the NF-{kappa}B subunit protein p65. These findings highlight the role of LMP1 as a mediator of EBV-host cell interactions and may indicate an important route by which it exerts its cellular growth transforming properties.

* Corresponding author. Mailing address: School of Biotechnology, Dublin City University, Dublin 9, Ireland. Phone: 353 1 7045600. Fax: 353 1 7045412. E-mail: Dermot.Walls{at}dcu.ie.

{dagger} Present address: Department of Biological Chemistry, UCLA School of Medicine, UCLA, Los Angeles, CA 90095-1737.

{ddagger} Present address: Department of Pathology, Children's Hospital, Harvard Medical School, Boston, MA 02115.

§ Present address: Schering-Plough (Brinny) Co., Innishannon, County Cork, Ireland.

|| Present address: Max Delbrueck Center, Berlin, Germany.

Journal of Virology, February 2004, p. 1800-1816, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1800-1816.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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