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Surface expression and endocytosis of the human cytomegalovirus-encoded chemokine receptor US28 is regulated by agonist-independent phosphorylation

Item Type:Article
Title:Surface expression and endocytosis of the human cytomegalovirus-encoded chemokine receptor US28 is regulated by agonist-independent phosphorylation
Creators Name:Mokros, T. and Rehm, A. and Droese, J. and Oppermann, M. and Lipp, M. and Hoepken, U.E.
Abstract:Human cytomegalovirus encodes the G protein-coupled chemokine receptor homologue US28 that binds several CC chemokines and sequesters extracellular chemokines from the environment of infected cells. Mechanistically, it has been shown that US28 undergoes rapid constitutive receptor endocytosis and recycling. Monoclonal antibodies were raised that allowed the characterization of a ligand-independent phosphorylation and low surface expression of the US28 receptor in transiently transfected HEK293A cells. Phosphoamino acid analysis defined C-terminal serine and threonine residues as phospho-acceptor sites for constitutive receptor phosphorylation. Coexpression of G protein-coupled receptor kinase-2 and US28 enhanced ligand-independent receptor phosphorylation. C-terminal serine to alanine mutagenesis of US28 resulted in a decreased phosphorylation rate that correlated with enhanced surface expression. Maximal surface expression was detected when all C-terminal serines were substituted. Exchange of all C-terminal serines also significantly reduced receptor endocytosis. Thus, constitutive US28 phosphorylation regulates receptor endocytosis and receptor surface display and may thereby provide a pathogenic mechanism for a potential decoy function of the virally encoded receptor.
Keywords:Amino Acid Sequence, Cell Line, Cell Membrane, Chemokine Receptors, Cytomegalovirus, Endocytosis, Enzyme Inhibitors, Fibroblasts, Inbred C57BL Mice, Molecular Sequence Data, NF-kappa B, Phosphorylation, RANTES, Recombinant Fusion Proteins, Reporter Genes, Site-Directed Mutagenesis, Viral Proteins, Animals, Cattle, Mice
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:277
Number:47
Page Range:45122-45128
Date:1 January 2002
PubMed:View item in PubMed

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