US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection

Abstract

Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.

Modulation of Innate Immune Signaling Pathways by Herpesviruses

“…Accordingly, the activated PKC phosphorylates caspase recruitment domain (CARD)-containing proteins (CARMA) and associate with IKKβ to activate NF-κB [100,101]. HCMV and KSHV encode several vGPCRs, which are homologous to the human IL-8R, and also activate NF-κB through distinct mechanisms [102,103]. These vGPCRs are constitutively active, although agonists can further promote vGPCR-mediated signaling.…”

“…These vGPCRs are constitutively active, although agonists can further promote vGPCR-mediated signaling. Paradoxically, vGPCRs are expressed in the lytic phase and implicated in pathogenesis of these herpesviruses, likely via both autocrine and paracrine mechanisms [102,103]. NF-κB activation by vGPCRs appears to be less robust than that induced by vFLIP and LMP1.…”

HCMV latency: what regulates the regulators?

“…It has been known for some time that US28 is expressed during latent infection of myeloid cells [45–49] but the functions of US28 have mostly been described for lytic infection. During the replication cycle of HCMV, US28 acts as a chemokine receptor homologue, binding CXXXC and CC chemokines [50, 51], but US28 can also signal constitutively [52, 53]. A comprehensive summary of US28 signalling functions during lytic infection, including cell type specificity, ligand interactions, and G-protein usage, was recently published [54].…”

US28: HCMV’s Swiss Army Knife

“…Targeting pUS28 as an antiviral against lytic infection may therefore prove less effective. However, as pUS28 is associated with pro-inflammatory and proliferative phenotypes, targeting pUS28 could serve as an additional effective treatment against CVD and tumor growth [ 147 , 164 ].…”