title: beta-Arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6.
abstract: Seven transmembrane receptors mediate diverse physiological responses including hormone action, olfaction, neurotransmission, and chemotaxis. Human D6 is a non-signaling seven-transmembrane receptor expressed on lymphatic endothelium interacting with most inflammatory CC-chemokines resulting in their rapid internalization. Here, we demonstrate that this scavenging activity is mediated by continuous internalization and constant surface expression of the receptor, a process involving the clathrin-coated pit-dependent pathway. D6 constitutively associates with the cytoplasmic adaptor beta-arrestin, and this interaction is essential for D6 internalization. An acidic region, but not the putative phosphorylation sites in the cytoplasmic tail of D6, is critical for receptor interaction with beta-arrestin and subsequent internalization. Neither the native D6 nor mutants uncoupled from beta-arrestin activate any G-protein-mediated signaling pathways. Therefore, D6 may be considered a decoy receptor structurally adapted to perform chemokine scavenging.
authors.affiliation: Centro di Eccellenza per l'Innovazione Diagnostica e Terapeutica (IDET), Institute of General Pathology, University of Milan, I-20133 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Galliera
authors.forename: Venkatakrishna R
authors.initials: VR
authors.lastname: Jala
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bonecchi
authors.forename: Paola
authors.initials: P
authors.lastname: Signorelli
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Massimo
authors.initials: M
authors.lastname: Locati
authors.forename: Bodduluri
authors.initials: B
authors.lastname: Haribabu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000737:chemistry / Q000502:physiology*; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008969:Molecular Sequence Data; D054447:Receptors, CCR10; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism*; D000071557:beta-Arrestins; D000097628:Chemokine Receptor D6
chemical_list: D019390:Arrestins; D054447:Receptors, CCR10; D019707:Receptors, Chemokine; D000071557:beta-Arrestins; D000097628:Chemokine Receptor D6