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Gene Review

US28  -  type 3 membrane protein; 7 transmembrane...

Human herpesvirus 5

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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


Biological context of HHV5gp145


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


  1. Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. Gao, J.L., Murphy, P.M. J. Biol. Chem. (1994) [Pubmed]
  2. The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Streblow, D.N., Soderberg-Naucler, C., Vieira, J., Smith, P., Wakabayashi, E., Ruchti, F., Mattison, K., Altschuler, Y., Nelson, J.A. Cell (1999) [Pubmed]
  3. Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. Casarosa, P., Menge, W.M., Minisini, R., Otto, C., van Heteren, J., Jongejan, A., Timmerman, H., Moepps, B., Kirchhoff, F., Mertens, T., Smit, M.J., Leurs, R. J. Biol. Chem. (2003) [Pubmed]
  4. Characterization of the rhesus cytomegalovirus US28 locus. Penfold, M.E., Schmidt, T.L., Dairaghi, D.J., Barry, P.A., Schall, T.J. J. Virol. (2003) [Pubmed]
  5. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Maussang, D., Verzijl, D., van Walsum, M., Leurs, R., Holl, J., Pleskoff, O., Michel, D., van Dongen, G.A., Smit, M.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. G-protein-coupled receptor (GPCR) kinase phosphorylation and beta-arrestin recruitment regulate the constitutive signaling activity of the human cytomegalovirus US28 GPCR. Miller, W.E., Houtz, D.A., Nelson, C.D., Kolattukudy, P.E., Lefkowitz, R.J. J. Biol. Chem. (2003) [Pubmed]
  7. Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28. Hulshof, J.W., Casarosa, P., Menge, W.M., Kuusisto, L.M., van der Goot, H., Smit, M.J., de Esch, I.J., Leurs, R. J. Med. Chem. (2005) [Pubmed]
  8. Endocytosis of the viral chemokine receptor US28 does not require beta-arrestins but is dependent on the clathrin-mediated pathway. Fraile-Ramos, A., Kohout, T.A., Waldhoer, M., Marsh, M. Traffic (2003) [Pubmed]
  9. Localization of HCMV UL33 and US27 in endocytic compartments and viral membranes. Fraile-Ramos, A., Pelchen-Matthews, A., Kledal, T.N., Browne, H., Schwartz, T.W., Marsh, M. Traffic (2002) [Pubmed]
  10. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. Casarosa, P., Bakker, R.A., Verzijl, D., Navis, M., Timmerman, H., Leurs, R., Smit, M.J. J. Biol. Chem. (2001) [Pubmed]
  11. Simian cytomegalovirus encodes five rapidly evolving chemokine receptor homologues. Sahagun-Ruiz, A., Sierra-Honigmann, A.M., Krause, P., Murphy, P.M. Virus Genes (2004) [Pubmed]
  12. Comparative sequence analysis of US28 gene of human cytomegalovirus strains isolated from HIV-positive patients. Goffard, A., Gault, E., Rozenberg, F., Moret, N., Hober, D., Dény, P. Virus Genes (2006) [Pubmed]
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