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MBC in Press, published online ahead of print December 9, 2004
Mol. Biol. Cell 10.1091/mbc.E04-08-0687

A more recent version of this article appeared on February 1, 2005
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Submitted on August 10, 2004
Revised on October 19, 2004
Accepted on December 1, 2004

Agonist-induced Endocytosis of Chemokine Receptor 5 (CCR5) Is Clathrin-dependent

Nathalie Signoret,* Lindsay Hewlett,* Silène Wavre,* Annegret Pelchen-Matthews,* Martin Oppermann,{dagger} and Mark Marsh*{ddagger}

*Cell Biology Unit, Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom; {dagger}Department of Immunology, Georg-August-University, 37075 Göttingen, Germany

Monitoring Editor: Jean Gruenberg

The signaling activity of several chemokine receptors, including CCR5, is in part controlled by their internalization, recycling and/or degradation. For CCR5, agonists such as the chemokine CCL5 induce internalization into early endosomes containing the transferrin receptor, a marker for clathrin-dependent endocytosis, but it has been suggested that CCR5 may also follow clathrin-independent routes of internalization. Here, we present a detailed analysis of the role of clathrin in chemokine-induced CCR5 internalization. Using CCR5-transfected cell lines, immunofluorescence and electron microscopy, we demonstrate that CCL5 causes the rapid redistribution of scattered cell surface CCR5 into large clusters that are associated with flat clathrin lattices. Invaginated clathrin-coated pits could be seen at the edge of these lattices and, in CCL5-treated cells, these pits contain CCR5. Receptors internalized via clathrin-coated vesicles follow the clathrin-mediated endocytic pathway, and depletion of clathrin with small interfering RNAs inhibits CCL5-induced CCR5 internalization. We found no evidence for CCR5 association with caveolae during agonist-induced internalization. However, sequestration of cholesterol with filipin interferes with agonist binding to CCR5, suggesting that cholesterol and/or lipid raft domains play some role in the events required for CCR5 activation before internalization.

{ddagger}Corresponding author. E-mail: m.marsh{at}ucl.ac.uk






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