Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor.
Human cytomegalovirus infects epithelial, smooth muscle, and white blood cells in vivo causing acute, latent, and chronic infections. 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. This suggested that US28 was originally copied from a human chemokine receptor gene, perhaps to provide the virus with a selective advantage through molecular mimicry. Chemokines regulate the trafficking and activation of mammalian leukocytes and activate calcium-mobilizing, heptahelical, G protein-coupled receptors. We now show that US28 encodes a promiscuous calcium-mobilizing receptor for the beta chemokines RANTES (regulated upon activation, normal T expressed and secreted), macrophage inflammatory protein-1 alpha, and monocyte chemoattractant protein-1, but not for the alpha chemokines interleukin-8 or gamma IP10. The chemokine selectivity of the US28 product is distinct from that of known mammalian beta chemokine receptors. This finding suggests a role for beta chemokines in the pathogenesis of human cytomegalovirus infection by transmembrane signaling via the product of US28.
Gao
J L
JL
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Murphy
P M
PM
D000595:Amino Acid Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D003587:Cytomegalovirus / Q000235:genetics*; D005814:Genes, Viral; D006801:Humans; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C515334:CCR2 protein, human; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic