Multiple roles for the carboxy-terminal tail of the chemokine scavenger D6. Export

@article{citeulike:2268845, abstract = {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 internalising 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 GFP-tagged beta-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 internalisation and effective scavenging of the chemokine CCL3. Even in the absence of the last 58 amino acids, D6 still initially internalises CCL3 but surprisingly, encounter with 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.}, address = {Division of Immunology, Infection and Inflammation, Glasgow University, Glasgow, Scotland. G12 8TA.}, author = {McCulloch, Clare V V. and Morrow, Valerie and Milasta, Sandra and Comerford, Iain and Milligan, Graeme and Graham, Gerard J J. and Isaacs, Neil W W. and Nibbs, Robert J B J.}, citeulike-article-id = {2268845}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M710128200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18201974}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18201974}, day = {17}, doi = {10.1074/jbc.M710128200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {chemokine\_receptor, d6, recycling}, month = {January}, posted-at = {2008-01-21 13:53:00}, priority = {2}, title = {Multiple roles for the carboxy-terminal tail of the chemokine scavenger D6.}, url = {http://dx.doi.org/10.1074/jbc.M710128200}, year = {2008} }

TY - JOUR ID - citeulike:2268845 L3 - citeulike-article-id:2268845 N2 - 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 internalising 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 GFP-tagged beta-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 internalisation and effective scavenging of the chemokine CCL3. Even in the absence of the last 58 amino acids, D6 still initially internalises CCL3 but surprisingly, encounter with 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. JF - J Biol Chem SN - 0021-9258 AD - Division of Immunology, Infection and Inflammation, Glasgow University, Glasgow, Scotland. G12 8TA. TI - Multiple roles for the carboxy-terminal tail of the chemokine scavenger D6. KW - chemokine_receptor KW - d6 KW - recycling AU - McCulloch, Clare V AU - Morrow, Valerie AU - Milasta, Sandra AU - Comerford, Iain AU - Milligan, Graeme AU - Graham, Gerard J AU - Isaacs, Neil W AU - Nibbs, Robert J B PY - 2008/01/17/ UR - http://dx.doi.org/10.1074/jbc.M710128200 ER -