scholarly journals Biased agonism and allosteric modulation of G protein-coupled receptor 183 - a 7TM receptor also known as Epstein-Barr virus-induced gene 2

2017 ◽  
Vol 174 (13) ◽  
pp. 2031-2042 ◽  
Author(s):  
Viktorija Daugvilaite ◽  
Christian Medom Madsen ◽  
Michael Lückmann ◽  
Clara Castello Echeverria ◽  
Andreas Walter Sailer ◽  
...  
Keyword(s):  
G Protein ◽  
Epstein Barr Virus ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptor ◽  
Biased Agonism ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled

scholarly journals The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

2009 ◽  
Vol 5 (1) ◽  
pp. e1000255 ◽  
Author(s):  
Jianmin Zuo ◽  
Andrew Currin ◽  
Bryan D. Griffin ◽  
Claire Shannon-Lowe ◽  
Wendy A. Thomas ◽  
...  
Keyword(s):  
G Protein ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
Class I ◽  
G Protein Coupled Receptor ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled ◽  
Mhc Class I Molecules

scholarly journals Cell transformation mediated by the Epstein–Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling

Oncogene ◽  
2010 ◽  
Vol 29 (31) ◽  
pp. 4388-4398 ◽  
Author(s):  
R Lyngaa ◽  
K Nørregaard ◽  
M Kristensen ◽  
V Kubale ◽  
M M Rosenkilde ◽  
...  
Keyword(s):  
G Protein ◽  
Epstein Barr Virus ◽  
Cell Transformation ◽  
G Protein Coupled Receptor ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled

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

2005 ◽  
Vol 79 (1) ◽  
pp. 441-449 ◽  
Author(s):  
Patrick S. Beisser ◽  
Dennis Verzijl ◽  
Yvonne K. Gruijthuijsen ◽  
Erik Beuken ◽  
Martine J. Smit ◽  
...  
Keyword(s):  
Protein Kinase ◽  
G Protein ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
G Protein Coupled Receptor ◽  
Lymphoma Cells ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled

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-κB-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-κB-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.

scholarly journals Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors.

1993 ◽  
Vol 67 (4) ◽  
pp. 2209-2220 ◽  
Author(s):  
M Birkenbach ◽  
K Josefsen ◽  
R Yalamanchili ◽  
G Lenoir ◽  
E Kieff
Keyword(s):  
G Protein ◽  
Epstein Barr Virus ◽  
Peptide Receptors ◽  
Barr Virus ◽  
Induced Genes ◽  
Epstein Barr ◽  
G Protein Coupled

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

2005 ◽  
Vol 79 (1) ◽  
pp. 536-546 ◽  
Author(s):  
Sarah J. Paulsen ◽  
Mette M. Rosenkilde ◽  
Jesper Eugen-Olsen ◽  
Thomas N. Kledal
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Kaposi's Sarcoma ◽  
Epstein Barr Virus ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled ◽  
Constitutively Active

ABSTRACT Both beta- and gammaherpesviruses encode G protein-coupled receptors (GPCRs) with unique pharmacological phenotypes and important biological functions. An example is ORF74, the γ2-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 γ1-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 γ1-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 Gαi. 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 Gαi. We suggest that EBV may use BILF1 to regulate Gαi-activated pathways during viral lytic replication, thereby affecting disease progression.

scholarly journals Identification and Functional Comparison of Seven-Transmembrane G-Protein-Coupled BILF1 Receptors in Recently Discovered Nonhuman Primate Lymphocryptoviruses

2014 ◽  
Vol 89 (4) ◽  
pp. 2253-2267 ◽  
Author(s):  
Katja Spiess ◽  
Suzan Fares ◽  
Alexander H. Sparre-Ulrich ◽  
Ellen Hilgenberg ◽  
Michael A. Jarvis ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
G Protein ◽  
Immune Evasion ◽  
Epstein Barr Virus ◽  
New World ◽  
Surface Expression ◽  
Barr Virus ◽  
Epstein Barr ◽  
G Protein Coupled ◽  
Insight Into

ABSTRACTCoevolution of herpesviruses with their respective host has resulted in a delicate balance between virus-encoded immune evasion mechanisms and host antiviral immunity. BILF1 encoded by human Epstein-Barr virus (EBV) is a 7-transmembrane (7TM) G-protein-coupled receptor (GPCR) with multiple immunomodulatory functions, including attenuation of PKR phosphorylation, activation of G-protein signaling, and downregulation of major histocompatibility complex (MHC) class I surface expression. In this study, we explored the evolutionary and functional relationships between BILF1 receptor family members from EBV and 12 previously uncharacterized nonhuman primate (NHP) lymphocryptoviruses (LCVs). Phylogenetic analysis defined 3 BILF1 clades, corresponding to LCVs of New World monkeys (clade A) or Old World monkeys and great apes (clades B and C). Common functional properties were suggested by a high degree of sequence conservation in functionally important regions of the BILF1 molecules. A subset of BILF1 receptors from EBV and LCVs from NHPs (chimpanzee, orangutan, marmoset, and siamang) were selected for multifunctional analysis. All receptors exhibited constitutive signaling activity via G protein Gαi and induced activation of the NF-κB transcription factor. In contrast, only 3 of 5 were able to activate NFAT (nuclear factor of activated T cells); chimpanzee and orangutan BILF1 molecules were unable to activate NFAT. Similarly, although all receptors were internalized, BILF1 from the chimpanzee and orangutan displayed an altered cellular localization pattern with predominant cell surface expression. This study shows how biochemical characterization of functionally important orthologous viral proteins can be used to complement phylogenetic analysis to provide further insight into diverse microbial evolutionary relationships and immune evasion function.IMPORTANCEEpstein-Barr virus (EBV), known as an oncovirus, is the only human herpesvirus in the genusLymphocryptovirus(LCV). EBV uses multiple strategies to hijack infected host cells, establish persistent infection in B cells, and evade antiviral immune responses. As part of EBV's immune evasion strategy, the virus encodes a multifunctional 7-transmembrane (7TM) G-protein-coupled receptor (GPCR), EBV BILF1. In addition to multiple immune evasion-associated functions, EBV BILF1 has transforming properties, which are linked to its high constitutive activity. We identified BILF1 receptor orthologues in 12 previously uncharacterized LCVs from nonhuman primates (NHPs) of Old and New World origin. As 7TM receptors are excellent drug targets, our unique insight into the molecular mechanism of action of the BILF1 family and into the evolution of primate LCVs may enable validation of EBV BILF1 as a drug target for EBV-mediated diseases, as well as facilitating the design of drugs targeting EBV BILF1.

scholarly journals Distinct Roles of Extracellular Domains in the Epstein-Barr Virus-Encoded BILF1 Receptor for Signaling and Major Histocompatibility Complex Class I Downregulation

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Suzan Fares ◽  
Katja Spiess ◽  
Emma T. B. Olesen ◽  
Jianmin Zuo ◽  
Sarah Jackson ◽  
...  
Keyword(s):  
G Protein ◽  
Mhc Class I ◽  
Epstein Barr Virus ◽  
Class I ◽  
Cysteine Residues ◽  
Conserved Residues ◽  
Barr Virus ◽  
Extracellular Domains ◽  
Epstein Barr ◽  
G Protein Coupled

ABSTRACTThe Epstein-Barr virus (EBV) BILF1 gene encodes a constitutively active G protein-coupled receptor (GPCR) that downregulates major histocompatibility complex (MHC) class I and induces signaling-dependent tumorigenesis. Different BILF1 homologs display highly conserved extracellular loops (ECLs) including the conserved cysteine residues involved in disulfide bridges present in class A GPCRs (GPCR bridge between transmembrane helix 3 [TM-3] and ECL-2) and in chemokine receptors (CKR bridge between the N terminus and ECL-3). In order to investigate the roles of the conserved residues in the receptor functions, 25 mutations were created in the extracellular domains. Luciferase reporter assays and flow cytometry were used to investigate the G protein signaling and MHC class I downregulation in HEK293 cells. We find that the cysteine residues involved in the GPCR bridge are important for both signaling and MHC class I downregulation, whereas the cysteine residues in the N terminus and ECL-3 are dispensable for signaling but important for MHC class I downregulation. Multiple conserved residues in the extracellular regions are important for the receptor-induced MHC class I downregulation, but not for signaling, indicating distinct structural requirements for these two functions. In an engineered receptor containing a binding site for Zn+2ions in a complex with an aromatic chelator (phenanthroline or bipyridine), a ligand-driven inhibition of both the receptor signaling and MHC class I downregulation was observed. Taken together, this suggests that distinct regions in EBV-BILF1 can be pharmacologically targeted to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation.IMPORTANCEG protein-coupled receptors constitute the largest family of membrane proteins. As targets of >30% of the FDA-approved drugs, they are valuable for drug discovery. The receptor is composed of seven membrane-spanning helices and intracellular and extracellular domains. BILF1 is a receptor encoded by Epstein-Barr virus (EBV), which evades the host immune system by various strategies. BILF1 facilitates the virus immune evasion by downregulating MHC class I and is capable of inducing signaling-mediated tumorigenesis. BILF1 homologs from primate viruses show highly conserved extracellular domains. Here, we show that conserved residues in the extracellular domains of EBV-BILF1 are important for downregulating MHC class I and that the receptor signaling and immune evasion can be inhibited by drug-like small molecules. This suggests that BILF1 could be a target to inhibit the signaling-mediated tumorigenesis and interfere with the MHC class I downregulation, thereby facilitating virus recognition by the immune system.

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