Disease relevance of HHV5gp145

• This finding suggests a role for beta chemokines in the pathogenesis of human cytomegalovirus infection by transmembrane signaling via the product of US28 [1].
• US28-mediated SMC migration provides a molecular basis for the correlative evidence that links HCMV to the acceleration of vascular disease [2].
• Moreover, VUF2274 inhibits US28-mediated HIV entry into cells [3].
• US28 induces migration of smooth muscle cells, a feature essential for the development of atherosclerosis, and may serve as a co-receptor for human immunodeficiency virus-type 1 entry into cells [3].
• In addition, we localized US28 and the rhesus CMV homolog RhUS28.5 to the envelope of infectious virions, suggesting a role in viral entry or cell tropism [4].

High impact information on HHV5gp145

• The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration [2].
• Our studies reveal that expression of US28 induces a proangiogenic and transformed phenotype by up-regulating the expression of vascular endothelial growth factor and enhancing cell growth and cell cycle progression [5].
• Hence, the constitutively activated chemokine receptor US28 might act as a viral oncogene and enhance and/or promote HCMV-associated tumor progression [5].
• Importantly, also in glioblastoma cells infected with the newly isolated clinical HCMV strain Titan, US28 was shown to be involved in the HCMV-induced angiogenic phenotype [5].
• Human cytomegalovirus encodes a GPCR termed US28 that is homologous to the human chemokine family of GPCRs but differs from the cellular receptors in that it maintains high constitutive activity in the absence of agonist [6].

Biological context of HHV5gp145

• A data base search revealed that the amino acid sequence of the putative protein encoded by open reading frame US28 of human cytomegalovirus is approximately 30% identical to those of the mammalian leukocyte receptors for alpha and beta chemokines [1].
• This result indicates that the carboxyl terminus of US28 contains an important signaling regulatory region and mutational analysis deleting carboxyl terminal serines identified serine 323 as a critical residue within this region [6].
• These results are consistent with the hypothesis that GRK phosphorylation and recruitment of beta-arrestin to the US28 viral GPCR attenuates signaling to the traditional Galphaq-stimulated inositol phosphate pathway [6].
• Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28 [7].
• Together, these data indicate that US28 endocytosis occurs via a clathrin-mediated mechanism but is independent of beta-arrestins [8].

Anatomical context of HHV5gp145

• In this study we have identified a small nonpeptidergic molecule (VUF2274) that inhibits US28-mediated phospholipase C activation in transiently transfected COS-7 cells and in HCMV-infected fibroblasts [3].
• In addition, VUF2274 fully displaces radiolabeled RANTES (regulated on activation normal T cell expressed and secreted) binding at US28, apparently with a noncompetitive behavior [3].
• With stable cell lines expressing these ORFs, we analyzed the homolog's binding and signaling characteristics across a wide range of chemokines and found one (RhUS28.5) to have a ligand binding profile similar to that of US28 [4].
• We previously reported that US28 is located in endocytic vesicles and undergoes constitutive endocytosis and recycling [9].
• Transient expression of US28 in COS-7 cells leads to the constitutive activation of phospholipase C and NF-kappaB signaling via G(q/11) protein-dependent pathways [10].

Associations of HHV5gp145 with chemical compounds

• Finally, by means of mutational analysis of US28, we have identified a glutamic acid in transmembrane 7 (TM 7), which is highly conserved among chemokine receptors, as a critical residue for VUF2274 binding to US28 [3].

Other interactions of HHV5gp145

• A related ORF named US27 is adjacent to US28, but no functions have been defined yet [11].

Analytical, diagnostic and therapeutic context of HHV5gp145

• Comparative sequence analysis of US28 gene of human cytomegalovirus strains isolated from HIV-positive patients [12].

References