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Review
. 2022 Sep 29;9(1):329-351.
doi: 10.1146/annurev-virology-100220-113942. Epub 2022 Jun 7.

Viral G Protein-Coupled Receptors Encoded by β- and γ-Herpesviruses

Mette M Rosenkilde  1 , Naotaka Tsutsumi  2 , Julius M Knerr  1 , Dagmar F Kildedal  3 , K Christopher Garcia  4
Affiliations
Review

Viral G Protein-Coupled Receptors Encoded by β- and γ-Herpesviruses

Mette M Rosenkilde et al. Annu Rev Virol. .

Abstract

Herpesviruses are ancient large DNA viruses that have exploited gene capture as part of their strategy to escape immune surveillance, promote virus spreading, or reprogram host cells to benefit their survival. Most acquired genes are transmembrane proteins and cytokines, such as viral G protein-coupled receptors (vGPCRs), chemokines, and chemokine-binding proteins. This review focuses on the vGPCRs encoded by the human β- and γ-herpesviruses. These include receptors from human cytomegalovirus, which encodes four vGPCRs: US27, US28, UL33, and UL78; human herpesvirus 6 and 7 with two receptors: U12 and U51; Epstein-Barr virus with one: BILF1; and Kaposi's sarcoma-associated herpesvirus with one: open reading frame 74, ORF74. We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from endogenous receptors. Finally, we briefly discuss the therapeutic targeting of vGPCRs as future treatment of acute and chronic herpesvirus infections.

Keywords: G protein signaling; GPCR structure; broad-spectrum ligand binding; chemokine receptor; herpesvirus.

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Figures

Figure 1
Figure 1
Four principles involving GPCRs and their ligands by which viruses regulate their host. Viruses (a) induce or reduce expression of endogenous receptors, (b) express vGPCRs, (c) express chemokines, or (d) express chemokine-binding proteins to impact the host immune system. Abbreviations: EBI, Epstein-Barr virus–induced gene; EBV, Epstein-Barr virus; GPCR, G protein–coupled receptor; HCMV, human cytomegalovirus; HHV, human herpesvirus; HSV, herpes simplex virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; vGPCR, viral G protein–coupled receptor; VZV, varicella-zoster virus. Figure adapted from images created with BioRender.com.
Figure 2
Figure 2
Overview of the complex interactions between chemokines and their chemokine receptors. Viral G protein–coupled receptors and the viral chemokines are highlighted in green. Figure adapted from References , , , and .
Figure 3
Figure 3
Shared properties of the vGPCRs. The vGPCRs share broad constitutive signaling through multiple pathways. They also bind multiple chemokines and, through internalization, clear them from the surroundings of the virus-infected cells. Through direct interaction and indirect crosstalk on signaling, they affect the function of endogenous and other viral receptors. Abbreviations: CREB, cAMP response element binding protein; GPCR, G protein–coupled receptor; HIF-1α, hypoxia-inducible factor 1α; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT, nuclear factor of activated T cells; vGPCR, viral G protein–coupled receptor. Figure adapted from images created with BioRender.com.
Figure 4
Figure 4
Structures of vGPCRs. (a) Cryo-EM structures of CX3CL1-US28-Gi (canonical-state), CXCL8-CXCR2-Gi, US27-Gi (canonical-like-state), and BILF1-Gi from the side view and the 90°-rotated top view. The models are colored in red (CX3CL1), green (US28), pink (CXCL8), blue (CXCR2), dark blue (US27), gray (BILF1), gold (Gα), cyan (Gβ), and purple (Gγ). ECL2s of BILF1 and US27 are highlighted in red. (b) Superimpositions of US28 model with CXCR2, US27, or BILF1 from the 90°-rotated bottom view from the side view in panel a, showing ligand-independent inactive and active conformation of US27 and BILF1, respectively. White arrowheads indicate relative TM positions between US27 and US28. (c) Crystal structures of apo US28, CX3CL1-US28, and CX3CL1.35-US28 assisted by a crystallization chaperone that is omitted for clarity. A ribbon model of apo US28 (green) is shown from two views with an extracellular cavity surface (red) on the left panels. The box indicates the region magnified on the right panels, showing binding modes between US28 (green) and CX3CL1s (red). For comparison, the apo US28 (light gray) is overlaid on the liganded US28 (green). Abbreviations: EBV, Epstein-Barr virus; ECL2, extracellular loop 2; HCMV, human cytomegalovirus; PDB, protein database; TM, transmembrane; vGPCR, viral G protein–coupled receptor. Figure prepared using UCSF ChimeraX (153).
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