title: The Epstein-Barr virus BILF1 gene encodes a G protein-coupled receptor that inhibits phosphorylation of RNA-dependent protein kinase.
abstract: 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-kappaB-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-kappaB-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 G(i/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.
authors.affiliation: Department of Medical Microbiology, University Hospital Maastricht, Maastricht, The Netherlands. pbe@lmib.azm.nl
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Beisser
authors.forename: Dennis
authors.initials: D
authors.lastname: Verzijl
authors.forename: Yvonne K
authors.initials: YK
authors.lastname: Gruijthuijsen
authors.forename: Erik
authors.initials: E
authors.lastname: Beuken
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Cathrien A
authors.initials: CA
authors.lastname: Bruggeman
authors.forename: Cornelis
authors.initials: C
authors.lastname: Vink
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: C495131:BILF1 protein, Epstein-Barr virus; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins; D019892:eIF-2 Kinase