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First published on September 12, 2007; DOI: 10.1124/mol.107.038422

0026-895X/07/7206-1497-1507$20.00
Mol Pharmacol 72:1497-1507, 2007

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Identification of a Postendocytic Sorting Sequence in CCR5

Maurine Delhaye, Audrey Gravot, Diana Ayinde, Florence Niedergang, Marc Alizon, and Anne Brelot

Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), Paris, France; and Institut National de la Santé et de la Recherche Médicale, U567, Paris, France

The chemokine receptor 5 (CCR5), a member of the G protein-coupled receptor family (GPCR), is used by human immunodeficiency virus type 1 (HIV-1) with a R5 tropism as an entry receptor in addition to CD4. It is a key target for an antiviral action aiming at inhibiting the HIV-1 entry process. Only few data are available today regarding the mechanism involved in the intracellular trafficking process of CCR5. Understanding how CCR5 cell surface expression is regulated is particularly important with regard to HIV-1 entry inhibition. We set out to investigate whether CCR5 molecular determinants were involved in the postendocytic recycling and degradative pathways. We constructed progressive deletion mutants of the C-terminal domain of CCR5 that we stably expressed in HEK293 cells. All of the deletion mutants were expressed at the cell surface and were functional HIV-1 receptors. The deletion mutants were internalized after stimulation, but they lost their ability to recycle to the plasma membrane. They were rerouted toward a lysosomal degradative pathway. We identified here a sequence of four amino acids, present at the extreme C terminus of CCR5, that is necessary for the recycling of the internalized receptor, independently of its phosphorylation. A detailed analysis of this sequence indicated that the four amino acids acted as a postsynaptic density 95/discs-large/zona occludens (PDZ) interacting sequence. These results show that the CCR5 cytoplasmic domain bears a sequence similar to the "recycling signals" previously identified in other GPCRs. Drugs able to disrupt the recycling pathway of CCR5 may constitute promising tools for therapeutic treatment.

Received May 23, 2007; accepted September 11, 2007

Address correspondence to: Anne Brelot, Institut Cochin, U567, Département de Biologie Cellulaire, 22 rue Méchain, 75014 Paris, France. E-mail: brelot{at}cochin.inserm.fr






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