Article Figures & Data
Figures
- Fig. 1.
Pharmacological properties of human herpesvirus–encoded GPCRs. Overview of the different viral GPCRs (colored GPCRs in the middle) encoded by the herpesviruses HCMV (HHV-5), HHV-6, HHV-7, EBV, or KSHV; their known ligands (top); and interacting G proteins (bottom). Their closest human chemokine homolog and the percentage of total homology are depicted. For each vGPCR, known signaling properties (constitutive or ligand-dependent) have been annotated.
- Fig. 2.
Major signaling pathways activated by human herpesvirus–encoded GPCRs in different disease settings. (A) Overview of the different (proliferative) signaling pathways activated by US28 (yellow arrows), UL33 (dark yellow arrows), ORF74 (pink arrows), and BILF1 (blue arrows) in cancer cells. Activation of some of these pathways results in the activation of cyclooxygenase 2 (COX2) and secretion of IL-6, PGE2, and VEGF. Secreted IL-6 activates the IL-6 receptor [consisting of the IL-6 receptor subunit (IL6R) and glycoprotein 130 (gp130)] . Activation of the IL-6 receptor results in the stimulation of the Janus kinase 1 (JAK1)-STAT3 pathway, leading to a feed-forward loop. Activation of these pathways contributes to several cancer hallmarks, including sustained proliferative signaling, tissue invasion, angiogenesis, and immune evasion. (B) Binding of CCL5 to US28 activates several pathways that result in smooth muscle cell migration in cardiovascular diseases. CCL5-mediated activation of US28 stimulates the Rho-associated protein kinase (ROCK) pathway and mitogen-activated protein kinase (MAPK) pathway and the formation of Src-mediated focal adhesion kinase (FAK) complexes, resulting in cytoskeletal changes, cell detachment, and subsequent cell migration. (C) US28 suppresses the major immediate early promotor (MIEP) and subsequent immediate early (IE) gene expression in early myeloid cells. US28 attenuates several pathways, including the CREB, activator protein 1 (AP-1) (via c-fos), and nuclear factor-κB (NF-κB) pathway. CREB-mediated signaling is inhibited by attentuation of the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen- and stress-activated kinase (MSK) 1 and CREB. By activation of the STAT3-inducible nitric oxide synthase (iNOS) pathway, US28 activation leads to increased nitric oxide (NO) levels, resulting in suppression of the MIEP. By suppression of MIEP, no IE expression is observed, resulting in a latent infection in early myeloid cells.
Tables
vGPCR (Virus and Lytic Expression Kinetics) Role in Lytic Infection Role in Latent Infection Role in Dissemination/Immune Evasion Orthologs UL33 (HCMV late) (Davis-Poynter et al., 1997) Dispensable (Margulies et al., 1996) but enhances spread in multistep growth analyses (van Senten et al., 2020a); constitutive signaling (Casarosa et al., 2003a) Expression detected but no role established (Cheng et al., 2017) Murine and rat models suggest roles in replication in salivary gland, latency, and dendritic cell trafficking (Frank et al., 2019) Murine - M33 rat - R33 UL78 (HCMV early) (Wagner et al., 2012) Dispensable (Michel et al., 2005) but important for entry into epithelial cells and replication in epi/endothelial cells (O’Connor and Shenk, 2012) Expression detected but no role established (Cheng et al., 2017) Murine and rat models suggest importance in replication in specific cell types in vivo (Oliveira and Shenk, 2001; Kaptein et al., 2003) Murine - M78 rat - R78 US27 (HCMV late) (Vieira et al., 1998; Chambers et al., 1999; Margulies and Gibson, 2007) Important for extracellular spread (O’Connor and Shenk, 2011); promotion of cell growth and survival (Tu and Spencer, 2014) Expression not detected (Cheng et al., 2017; Shnayder et al., 2018) Highly conserved but in vivo role unclear (Stegman and Margulies, 2017; Frank et al., 2019) Present in primate CMVs but not rodent CMVs (Alcendor et al., 2009) US28 (HCMV early) (Vieira et al., 1998) Dispensable (Vieira et al., 1998; Humby and O’Connor, 2015); enhances infection of epithelial cells and smooth muscle cells (Noriega et al., 2014; Lollinga et al., 2017); constitutive and ligand-induced signaling (Krishna et al., 2018) Required for latency in in vitro models (Humby and O’Connor, 2015; Krishna et al., 2017a; Zhu et al., 2018); required for reactivation in humanized mice (Crawford et al., 2019) Induces cell migration and adhesion (Melnychuk et al., 2004; Vomaske et al., 2009; Hjorto et al., 2013; Wu and Miller, 2016; Farrell et al., 2018; Aslam et al., 2019); chemokine sink (Randolph-Habecker et al., 2002); myeloid differentiation (Zhu et al., 2018; Crawford et al., 2019) Present in primate CMVs but not rodent CMVs (Alcendor et al., 2009); five rhesus CMV US28 homologs characterized U12 (HHV-6A/B late) (Isegawa et al., 1998) Ligand-induced signaling (Isegawa et al., 1998); likely dispensable for viral replication (Dominguez et al., 1999) Unknown Unknown Homologs not functionally characterized U51 (HHV-6A/B early) (Menotti et al., 1999) Enhances viral replication (Zhen et al., 2005) Unknown Leukocyte migration/immunomodulation (Catusse et al., 2008) Homologs not functionally characterized U12 (HHV-7) Ligand-induced signaling (Nakano et al., 2003; Tadagaki et al., 2005) Unknown Unknown Homologs not functionally characterized U51 (HHV-7) Ligand-induced signaling (Tadagaki et al., 2005) Unknown Unknown Homologs not functionally characterized BILF1 (EBV early) Immune evasion (cell intrinsic and extrinsic) (Arfelt et al., 2015; Morales-Sánchez and Fuentes-Panana, 2018) not required for lytic replication (Zuo et al., 2011) Expressed at low levels (Tierney et al., 2015) Likely immune evasion including evasion of cytotoxic T-cell recognition BILF1 homologs characterized in primate lymphocryptoviruses (Spiess et al., 2015a) ORF74 (KSHV early) (Chiou et al., 2002) Necessary for efficient lytic replication (Sandford et al., 2009) Expression kept at low levels (Vischer et al., 2014); possible reactivation from latency (Chen et al., 2009; Sandford et al., 2009) Murine models indicate important roles in reactivation from latency (Moorman et al., 2003; López-Rodríguez et al., 2019) MHV68 ORF74 (Virgin et al., 1997) Molecule Class Molecule Name/Scaffold Mode of Action Infection State In Vitro/In Vivo Functional Effect Reference Small molecule Piperazinyldibenzothiepins; cinchonine derivates; cinchonidines derivates; arylamines; benzamides Antagonists — In vitro Ligand blocking Vischer et al. (2014) Methiothepin; Octoclothepin; S-(−)-Iodobenzamide Antagonist/partial inverse agonist — In vitro Ligand blocking and partial inhibition of US28 constitutive activity Vischer et al. (2010) VUF2274 Antagonist/full inverse agonist Latent infection In vitro Full reactivation of latently infected cells resulting in T-cell–mediated cell death Casarosa et al. (2003b); Krishna et al. (2017a) Derivates of flavonoids; biphenyl amides; CX3CR1 antagonists; VUF2274 Agonist; antagonist; inverse agonist — In vitro Ligand blocking/enhanced US28 signaling/partial inhibition of US28 constitutive activity Kralj et al. (2011), (2013), (2014); Lückmann et al. (2017); Amărandi et al. (2018) Nanobody US28-Nb Antagonist Cancer setting In vitro Ligand blocking Heukers et al. (2018) Bivalent US28-Nb Antagonist/partial inverse agonist Cancer setting In vitro/in vivo Partial inhibition of US28-mediated enhanced glioblastoma tumor growth Heukers et al. (2018) VUN100-PS Antagonist/photosensitizer-induced cell death Cancer setting In vitro Selective killing of US28-expressing glioblastoma cells De Groof et al. (2019b) Toxin-coupled chemokine F49A-FTP Toxin-induced cell death Lytic infection In vitro/in vivo Selective killing of HCMV-infected cells Spiess et al. (2015b) Latent infection In vitro Krishna et al. (2017b)
In this issue
Viral GPCRs as Attractive Targets
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- Article
- Visual Overview
- Abstract
- I. Family of Viral G Protein–Coupled Receptors
- II. Viral G Protein–Coupled Receptors in a Viral Setting
- III. Role of Viral G Protein–Coupled Receptors in Disease
- IV. Viral G Protein–Coupled Receptor–Targeting Modulators and Therapeutics
- V. Concluding Remarks and Future Perspectives
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