Abstract
US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV). The US28 protein (pUS28) is a potent signaling molecule that alters a variety of cellular pathways that ultimately alter the host cell environment. This viral GPCR is expressed not only in the context of lytic replication but also during viral latency, highlighting its multifunctional properties. pUS28 is a functional GPCR, and its manipulation of multiple signaling pathways likely impacts HCMV pathogenesis. Herein, we will discuss the impact of pUS28 on both lytic and latent infection, pUS28-mediated signaling and its downstream consequences, and the influence this viral GPCR may have on disease states, including cardiovascular disease and cancer. We will also discuss the potential for and progress towards exploiting pUS28 as a novel therapeutic to combat HCMV.
Highlights
US28 is one of four G protein coupled receptors (GPCRs) encoded by human cytomegalovirus (HCMV)
HCMV is a ubiquitous member of the herpesviridae family, which characteristically establishes lifelong, latent infections that are largely asymptomatic in healthy individuals, as the virus is controlled by a robust immune response
HCMV-encoded chemokine receptor homologues appear to interact with other such receptors. Both pUL33 and pUL78 heteromerize with CCR5 and CXCR4, which negatively impacts the respective signaling functions of these cellular receptors when overexpressed in the monocytic THP-1 cell line This suggests that perhaps the HCMV-encoded chemokine receptor homologues may have evolved to modulate the activity of each other, or of cellular GPCRs, in certain biological scenarios
Summary
GPCRs are seven-transmembrane signaling proteins that represent a large and diverse group of eukaryotic signaling proteins with a transmembrane structure, which respond to an array of different stimuli acting via a common signaling mechanism [10]. Gαi and Gαq have wide tissue distribution, while Gα15 and Gα16 display myeloid and lymphoid lineage specificity [37,38] This wide range of ligand binding, combined with a wide selection of Gα proteins explains how the structurally similar GPCRs can induce multiple, yet distinct signaling pathways, altering various cellular processes that result in a milieu of phenotypes across the whole of biology. HCMV-encoded chemokine receptor homologues appear to interact with other such receptors Both pUL33 and pUL78 heteromerize with CCR5 and CXCR4, which negatively impacts the respective signaling functions of these cellular receptors when overexpressed in the monocytic THP-1 cell line [41]; Table 1) This suggests that perhaps the HCMV-encoded chemokine receptor homologues may have evolved to modulate the activity of each other, or of cellular GPCRs, in certain biological scenarios. PUS28structure overexpression and in the modulated in response pUS28 overexpression is found in
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