HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks

Trends Pharmacol Sci. 2006 Jan;27(1):56-63. doi: 10.1016/j.tips.2005.11.006. Epub 2005 Dec 13.


Several herpesviruses encode G-protein-coupled receptor (vGPCR) proteins that are homologous to human chemokine receptors. In contrast to chemokine receptors, many vGPCRs signal in a ligand-independent (constitutive) manner. Such constitutive signaling is of major significance because various pathologies are associated with activating GPCR mutations. Constitutive activity of the human herpesvirus 8-encoded GPCR (ORF74), for example, is essential for its oncogenic potential to cause angioproliferative Kaposi's sarcoma-like lesions. The human cytomegalovirus (HCMV) encodes four GPCRs, of which US28 and UL33 display constitutive activity in transfected, but also HCMV-infected, cells. In addition, US28 is activated by a broad spectrum of chemokines. Furthermore, both US28 and UL33 show promiscuous G-protein coupling, whereas chemokine receptors activate primarily G(i/o) proteins. Thus, these vGPCRs are versatile signaling devices, reprogramming cellular signaling networks to modulate cellular function after infection. By these means, these HCMV-encoded receptors might contribute to HCMV-related pathologies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Humans
  • Molecular Sequence Data
  • Receptors, Chemokine / physiology*
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction / physiology*
  • Viral Proteins / physiology*


  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • UL33 protein, human cytomegalovirus
  • US27 protein, human cytomegalovirus
  • US28 receptor, Cytomegalovirus
  • Viral Proteins