Human cytomegalovirus encodes three G protein-coupled receptor homologues

Abstract

Human cytomegalovirus (HCMV) is a herpesvirus with a genome of 230 kilobases (Kb) encoding about 200 genes. Although infection is generally innocuous, HCMV causes serious congenital and neonatal disease, and is a dangerous opportunistic pathogen in immune-deficient individuals. We have identified a family of three HCMV genes which encode polypeptides containing seven putative membrane-spanning domains, and a series of well-defined motifs characteristic of the rhodopsin-like G protein-coupled receptors (GCRs). By these criteria all three of the HCMV sequences are homologous to cellular GCRs. Members of this receptor family function in visual signal transduction, regulation of homeostasis, and development, and include known and potential oncogenes. These receptors are activated by photons or small molecules such as neurotransmitters, and glycoprotein hormones. The finding of viral-encoded GCR homologues implies a further level of complexity in the interactions between HCMV and its host, and may provide a potential pathway for virally transformed cell proliferation. Their identification could permit the development of a novel class of antiviral drugs analogous to beta-adrenergic receptor antagonists.

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

“…Previously, four genes encoding vGPCRs have been identified in the HCMV genome (US27, US28, UL33, and UL78) (4). Although a recent study has suggested that the HCMV genome contains an additional 11 genes that putatively encode proteins possessing 7 transmembrane domains (5), these genes seem to lack other sequences characteristic of the family of GPCR genes.…”

“…Within the HCMV genome, four genes encoding GPCRs have previously been identified (US27, US28, UL33, and UL78) (4). Recently, it has been suggested that the HCMV genome may contain additional putative GPCR genes (5).…”

Cell growth control by G protein-coupled receptors: from signal transduction to signal integration

“…Sequences encoding functional GPCRs have also been found in the genome of a number of DNA viruses, including human cytomegalovirus (HCMV) (Bankier et al, 1991;Chee et al, 1990), herpes virus saimiri (HVS) (Nicholas et al, 1992) and Kaposi's sarcoma associated herpesvirus (KSHV) (Arvanitakis et al, 1997). The HCMV, which infects leukocytes, ®broblasts and epithelial cells, contains in its genome three predicted open reading frames, UL27, UL28, and UL33, encoding typical GPCRs, which are believed to represent functional chemokine receptors (Ahuja and Murphy, 1993;Neote et al, 1993).…”

Deletion of the R78 G protein-coupled receptor gene from rat cytomegalovirus results in an attenuated, syncytium-inducing mutant strain

“…These genes can be arranged into four groups based on sequence homology, genome location, and function of the respective gene product. One group (the US28 family) consists of two GCR genes: US27 and US28 (23). Both are exclusively present within an unconserved region of the HCMV genome (22).…”

“…The KSHV chemokine receptor was also shown to stimulate cellular proliferation (4), transformation, and angiogenesis (7). A distinctive set of chemokine-like receptors is exclusively encoded by betaherpesviruses: HCMV UL33 (23), rat cytomegalovirus (RCMV) R33 (9), murine cytomegalovirus (MCMV) M33 (54), and human herpesvirus 6 and 7 (HHV-6 and -7) U12 (33,49). Recently, we found that the RCMV R33 gene is essential for the pathogenesis of viral infection in vivo and that unlike wild-type (wt) virus, an RCMV R33 null mutant could neither enter nor replicate in salivary gland epithelial cells of infected rats (9).…”