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Journal of Virology, January 2005, p. 441-449, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.441-449.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Epstein-Barr Virus BILF1 Gene Encodes a G Protein-Coupled Receptor That Inhibits Phosphorylation of RNA-Dependent Protein Kinase

Patrick S. Beisser,1* Dennis Verzijl,2 Yvonne K. Gruijthuijsen,1 Erik Beuken,1 Martine J. Smit,2 Rob Leurs,2 Cathrien A. Bruggeman,1 and Cornelis Vink1

Department of Medical Microbiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht,1 Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Free University, Amsterdam, The Netherlands2

Received 7 May 2004/ Accepted 12 August 2004

Epstein-Barr virus (EBV) infection is associated with many lymphoproliferative diseases, such as infectious mononucleosis and Burkitt's lymphoma. Consequently, EBV is one of the most extensively studied herpesviruses. Surprisingly, a putative G protein-coupled receptor (GPCR) gene of EBV, BILF1, has hitherto escaped attention, yet BILF1-like genes are conserved among all known lymphocryptovirus species, suggesting that they play a pivotal role in viral infection. To determine the function of EBV BILF1, the activity of this gene and its products was studied. BILF1-specific mRNA was detected in various EBV-positive cell types and found to be expressed predominantly during the immediate early and early phases of infection in vitro. Interestingly, in COS-7 cells transfected with BILF1 expression constructs, a decrease in forskolin-induced CRE-mediated transcription was measured, as well as an increase in NF-{kappa}B-mediated transcription. In contrast, CRE-mediated transcription was increased in EBV-positive Burkitt's lymphoma cells as well as EBV-positive lymphoblastoid B cells transfected with BILF1, whereas NF-{kappa}B-mediated transcription levels remained unaffected in these cells. All observed activities were sensitive to treatment with pertussis toxin, indicating that the BILF1-encoded protein mediates these activities by coupling to G proteins of the Gi/o class. Finally, reduced levels of phosphorylated RNA-dependent antiviral protein kinase were observed in COS-7 and Burkitt's lymphoma cells transfected with BILF1. Neither of the observed effects required a ligand to interact with the BILF1 gene product, suggesting that BILF1 encodes a constitutively active GPCR capable of modulating various intracellular signaling pathways.

* Corresponding author. Mailing address: Department of Medical Microbiology, University Hospital Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. Phone: 31 43 3876642. Fax: 31 43 3876643. E-mail: pbe{at}lmib.azm.nl.

Journal of Virology, January 2005, p. 441-449, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.441-449.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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