Why Are Cytomegalovirus-Encoded G-Protein-Coupled Receptors Essential for Infection but Only Variably Conserved?

Abstract

Cytomegaloviruses (CMVs) encode viral G-protein-coupled receptors (vGPCRs) that have diverged from their cellular homologues to perform new functions. Human cytomegalovirus (HCMV) encodes four vGPCRs: UL33, UL78, US27, and US28, which contribute to viral pathogenesis, cellular signalling, and latency. While the role of US28 in chemokine signalling and viral latency is well characterised, the functions of other vGPCRs remain incompletely understood. Rodent cytomegaloviruses only have homologues to UL33 and UL78, while primates have two to five additional GPCRs which are homologues of US27 and US28. Different CMVs appear to have evolved vGPCRs with functions specific to infection of their respective host. As non-human CMVs are used as model organisms to understand clinical cytomegalovirus disease and develop vaccines and antivirals, understanding the differences between these vGPCRs helps researchers understand critical differences between their models. This review aims to address the differences between CMV vGPCRs, and how these differences may affect models of CMV disease to facilitate future research.

Keywords: G-protein coupled receptors (GPCRs); animal models; cytomegalovirus (CMV); signalling; therapeutics.

Figure 1

General diagram of GPCR functions. Upon binding ligands, GPCRs exchange GDP for GTP on the associated Gα protein, leading to dissociation and lateral diffusion of Gα and Gβ/γ. Both complexes have downstream signalling functions with Gβ/γ also acting to sequester and inhibit Gα.

Figure 2

US28 signalling functions during latency, adapted from Elder et al. [118]. US28 signals during latency to repress MIEP activation and downstream HCMV gene expression. Shown here are US28 activation of STAT3-iNOS-NO [112], attenuation of NF-κB [50], and activation of EphA2 [119], which leads to downstream attenuation of ERK-MSK-CREB [50] and fos [120]. NF-κB, p-CREB, and fos-jun (AP-1) directly bind and activate the MIEP in the absence of US28 [50,120]. The mechanism for NO and CTCF [115] suppression of the MIEP is less clear. Red crosses indicate reduced activity in the presence of US28.

Figure 3

Tree of life showing the evolution of vGPCRs. Every CMV, including those of rodents and New World monkeys, has a homologue of UL33 and UL78 (brown tree trunk). Great apes have US27 and US28 (red branch), while other Old World monkeys have 5 homologues of US28 (green branch).