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Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1
ID
Tsutsumi, Naotaka
(
Author
),
ID
Qu, Qianhui
(
Author
),
ID
Mavri, Maša
(
Author
),
ID
Baggesen, Maibritt S.
(
Author
),
ID
Maeda, Shoji
(
Author
),
ID
Waghray, Deepa
(
Author
),
ID
Berg, Christian
(
Author
),
ID
Kobilka, Brian K.
(
Author
),
ID
Rosenkilde, Mette Marie
(
Author
),
ID
Skiniotis, Georgios
(
Author
),
ID
Garcia, K. Christopher
(
Author
)
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Abstract
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.
Language:
English
Keywords:
Epstein-Barr virus
,
G protein
,
G protein-coupled receptor
,
GPCR
,
cryo-EM
,
immune evasion
,
ligand-indpendent signaling
,
receptor
,
signaling
,
viral GPCR
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
VF - Veterinary Faculty
Publication status:
Published
Publication version:
Version of Record
Publication date:
01.01.2021
Year:
2021
Number of pages:
Str. 1405-1416
Numbering:
Vol. 54, no. 7
PID:
20.500.12556/RUL-137938
UDC:
636.09:616.9:578
ISSN on article:
1097-4180
DOI:
10.1016/j.immuni.2021.06.001
COBISS.SI-ID:
110440195
Publication date in RUL:
06.07.2022
Views:
630
Downloads:
114
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Record is a part of a journal
Title:
Immunity
Shortened title:
Immunity
Publisher:
Cell Press
ISSN:
1097-4180
COBISS.SI-ID:
18973735
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Projects
Funder:
NIH - National Institutes of Health
Project number:
R01AI125320
Funder:
Other - Other funder or multiple funders
Funding programme:
Kristen and Freddy Johansens Fundation
Project number:
2017-112697
Funder:
Other - Other funder or multiple funders
Funding programme:
Lundbeck Foundation
Project number:
R242-2017-409
Funder:
Other - Other funder or multiple funders
Funding programme:
Novo Nordisk Foundation
Project number:
NNF 17OC0029222
Funder:
Other - Other funder or multiple funders
Funding programme:
Human Science Frontier Program Organization
Project number:
LT000011/2016-L
Funder:
ARRS - Slovenian Research Agency
Funding programme:
Young Researcher PhD program
Funder:
ARRS - Slovenian Research Agency
Project number:
P4-0053
Name:
Endokrini, imunski in encimski odzivi pri zdravih in bolnih živalih
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