Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1.
Animals
Binding Sites
/ immunology
Cell Line
Chemokines
/ immunology
Cryoelectron Microscopy
/ methods
Epstein-Barr Virus Infections
/ immunology
HEK293 Cells
Herpesvirus 4, Human
/ immunology
Humans
Immunologic Factors
/ immunology
Protein Binding
/ immunology
Receptors, G-Protein-Coupled
/ immunology
Sf9 Cells
Signal Transduction
/ immunology
Viral Proteins
/ immunology
EBV
Epstein-Barr virus
G protein
G protein-coupled receptor
GPCR
cryo-EM
immune evasion
ligand-indpendent signaling
receptor
signaling
viral GPCR
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
13 07 2021
13 07 2021
Historique:
received:
19
08
2020
revised:
21
03
2021
accepted:
01
06
2021
pubmed:
4
7
2021
medline:
15
9
2021
entrez:
3
7
2021
Statut:
ppublish
Résumé
Epstein-Barr virus (EBV) encodes a G protein-coupled receptor (GPCR) termed BILF1 that is essential for EBV-mediated immunosuppression and oncogenesis. BILF1 couples with inhibitory G protein (Gi), the major intracellular signaling effector for human chemokine receptors, and exhibits constitutive signaling activity; the ligand(s) for BILF1 are unknown. We studied the origins of BILF1's constitutive activity through structure determination of BILF1 bound to the inhibitory G protein (Gi) heterotrimer. The 3.2-Å resolution cryo-electron microscopy structure revealed an extracellular loop within BILF1 that blocked the typical chemokine binding site, suggesting ligand-autonomous receptor activation. Rather, amino acid substitutions within BILF1 transmembrane regions at hallmark ligand-activated class A GPCR "microswitches" stabilized a constitutively active BILF1 conformation for Gi coupling in a ligand-independent fashion. Thus, the constitutive activity of BILF1 promotes immunosuppression and virulence independent of ligand availability, with implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.
Identifiants
pubmed: 34216564
pii: S1074-7613(21)00245-4
doi: 10.1016/j.immuni.2021.06.001
pmc: PMC8282746
mid: NIHMS1713675
pii:
doi:
Substances chimiques
BILF1 protein, Epstein-Barr virus
0
Chemokines
0
Immunologic Factors
0
Receptors, G-Protein-Coupled
0
Viral Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1405-1416.e7Subventions
Organisme : NIAID NIH HHS
ID : R01 AI125320
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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