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J. Biol. Chem., Vol. 283, Issue 12, 7972-7982, March 21, 2008

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Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6^*

Clare V. McCulloch, Valerie Morrow, Sandra Milasta, Iain Comerford¹, Graeme Milligan, Gerard J. Graham, Neil W. Isaacs^¶, and Robert J. B. Nibbs²

From the Division of Immunology, Infection and Inflammation, Faculty of Biomedical and Life Sciences, ^¶Department of Chemistry, Glasgow University, Glasgow G12 8TA, Scotland, United Kingdom

D6 is a heptahelical receptor that suppresses inflammation and tumorigenesis by scavenging extracellular pro-inflammatory CC chemokines. Previous studies suggested this is dependent on constitutive trafficking of stable D6 protein to and from the cell surface via recycling endosomes. By internalizing chemokine each time it transits the cell surface, D6 can, over time, remove large quantities of these inflammatory mediators. We have investigated the role of the conserved 58-amino acid C terminus of human D6, which, unlike the rest of the protein, shows no clear homology to other heptahelical receptors. We show that, in human HEK293 cells, a serine cluster in this region controls the constitutive phosphorylation, high stability, and intracellular trafficking itinerary of the receptor and drives green fluorescent protein-tagged β-arrestins to membranes at, and near, the cell surface. Unexpectedly, however, these properties, and the last 44 amino acids of the C terminus, are dispensable for D6 internalization and effective scavenging of the chemokine CCL3. Even in the absence of the last 58 amino acids, D6 still initially internalizes CCL3 but, surprisingly, exposure to ligand inhibits subsequent CCL3 uptake by this mutant. Progressive scavenging is therefore abrogated. We conclude that the heptahelical body of D6 on its own can engage the endocytotic machinery of HEK293 cells but that the C terminus is indispensable for scavenging because it prevents initial chemokine engagement of D6 from inhibiting subsequent chemokine uptake.

Received for publication, December 12, 2007 , and in revised form, January 10, 2008.

^* This work was supported by the Biotechnology and Biological Sciences Research Council (to C. V. M., G. J. G., N. W. I., and R. J. B. N.), Cancer Research UK (to V. M., I. C., and R. J. B. N.), and The Wellcome Trust (to S. M. and G. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, 5005 South Australia, Australia.

² To whom correspondence should be addressed: Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, Glasgow University, Glasgow G12 8TA, Scotland, UK. Tel.: 44-141-330-3960; Fax: 44-141-330-4297; E-mail: r.nibbs{at}clinmed.gla.ac.uk.

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