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Journal of Virology, January 2005, p. 536-546, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.536-546.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus-Encoded BILF1 Is a Constitutively Active G Protein-Coupled Receptor

Sarah J. Paulsen,1 Mette M. Rosenkilde,2 Jesper Eugen-Olsen,1 and Thomas N. Kledal1*

Clinical Research Unit, Copenhagen University Hospital, Hvidovre,1 Laboratory for Molecular Pharmacology, Department of Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark2

Received 16 June 2004/ Accepted 30 August 2004

Both beta- and gammaherpesviruses encode G protein-coupled receptors (GPCRs) with unique pharmacological phenotypes and important biological functions. An example is ORF74, the {gamma}2-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded GPCR, which is highly constitutively active and considered the key oncogene in Kaposi's sarcoma pathogenesis. In contrast, the current annotation of the Epstein-Barr virus (EBV) genome does not reveal any GPCR homolog encoded by this human oncogenic {gamma}1-herpesvirus. However, by employing bioinformatics, we recognized that the previously established EBV open reading frame BILF1 indeed encodes a GPCR. Additionally, BILF1 is a member of a new family of related GPCRs exclusively encoded by {gamma}1-herpesviruses. Expression of hemagglutinin-tagged BILF1 in the HEK293 epithelial cell line revealed that BILF1 is expressed as an approximately 50-kDa glycosylated protein. Immunocytochemistry and confocal microscopy revealed that BILF1 localizes predominantly to the plasma membrane, similar to the localization of KSHV ORF74. Using chimeric G proteins, we found that human and rhesus EBV-encoded BILF1 are highly potent constitutively active receptors, activating G{alpha}i. Furthermore, BILF1 is able to inhibit forskolin-triggered CREB activation via stimulation of endogenous G proteins in a pertussis toxin-sensitive manner, verifying that BILF1 signals constitutively through G{alpha}i. We suggest that EBV may use BILF1 to regulate G{alpha}i-activated pathways during viral lytic replication, thereby affecting disease progression.

* Corresponding author. Mailing address: Clinical Research Unit #136, H:S Hvidovre Hospital, Kettegaards Allé 30-31, 2650 Hvidovre, Denmark. Phone: 45 36322403. Fax: 45 36323797. E-mail: kledal{at}biobase.dk.

Journal of Virology, January 2005, p. 536-546, Vol. 79, No. 1
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.1.536-546.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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