4.8 Article

Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus-encoded G protein-coupled receptor BILF1

Journal

IMMUNITY
Volume 54, Issue 7, Pages 1405-+

Publisher

CELL PRESS
DOI: 10.1016/j.immuni.2021.06.001

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Funding

  1. NIH [R01AI125320]
  2. Kirsten and Freddy Johansens Foundation [2017-112697]
  3. Lundbeck Foundation [R242-2017-409]
  4. Novo Nordisk Foundation [NNF17OC0029222]
  5. Human Science Frontier Program Organization [LT000011/2016-L]
  6. Slovenian Research Agency [P40053]

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The study reveals that the EBV receptor BILF1 has constitutive signaling activity promoting immunosuppression and virulence independent of ligand availability. This has implications for the function of GPCRs encoded by related viruses and for therapeutic targeting of EBV.
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-angstrom 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.

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