![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 14, Issue 8, 3305-3324, August 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Laboratory of Molecular Microbiology, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland
20892;
¶ Laboratory of Host Defenses, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Maryland 20892;
# Laboratory of Clinical Investigation, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, Maryland
20892; and
Cell Biology and Metabolism Branch, National Institute of Child Health and
Human Development, National Institutes of Health, Bethesda, Maryland
20892
Submitted November 6, 2002;
Revised April 1, 2003;
Accepted April 4, 2003
Monitoring Editor: Suzanne Pfeffer
Desensitization of the chemokine receptors, a large class of G protein–coupled receptors, is mediated in part by agonist-driven receptor endocytosis. However, the exact pathways have not been fully defined. Here we demonstrate that the rate of ligand-induced endocytosis of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease.
Abbreviations used: AOP-RANTES, aminooxypentane-regulated on activation, normal T-cell expressed and secreted; APC, allophycocyanin; Arf6, ADP-ribosylation factor 6; CCV, clathrin-coated vesicles; CHO, Chinese hamster ovary; CKRs, chemokine receptors; CTx-B, B subunit of cholera toxin; C-terminal, carboxy-terminal; C-tail, carboxy-terminal tail; DRMs, detergent resistant membranes; EGFR, epidermal growth factor receptor; FITC, fluorescein isothiocyanate conjugated; GPCRs, G protein–coupled receptors; GPI, glycosyl phosphatidylinositol; GRKs, G protein–coupled receptor kinases; HEK, human embryonic kidney; IL-2 or IL-8, interleukin-2 or -8; LDL, low-density lipoprotein; MFV, mean fluorescence value; MHC-I, class I major histocompatibility; MIP, macrophage inflammatory protein; M-tropic, macrophage tropic; N-terminal, amino-terminal; PBL, peripheral blood lymphocyte; PE, phycoerythrin; PFA, paraformaldehyde; RT, room temperature; SDF, stromal derived factor; Tfn, transferrin; Tfn-R, transferrin receptor; TM, transmembrane; TR, Texas Red; T-tropic, T-cell tropic; wt, wild-type.
Present address: INRS-Institut Armand-Frappier, Université du
Québec, 531 des Prairies, Laval (Québec), Canada H7V 1B7.
Corresponding author. E-mail address:
aradhana{at}helix.nih.gov
or
sv1s{at}nih.gov.
This article has been cited by other articles:
|
|
 |
|
  G. O'Boyle, P. Mellor, J. A. Kirby, and S. Ali Anti-inflammatory therapy by intravenous delivery of non-heparan sulfate-binding CXCL12 FASEB J, November 1, 2009; 23(11): 3906 - 3916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Barroso-Gonzalez, J.-D. Machado, L. Garcia-Exposito, and A. Valenzuela-Fernandez Moesin Regulates the Trafficking of Nascent Clathrin-coated Vesicles J. Biol. Chem., January 23, 2009; 284(4): 2419 - 2434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Eugenin, S. Morgello, M. E. Klotman, A. Mosoian, P. A. Lento, J. W. Berman, and A. D. Schecter Human Immunodeficiency Virus (HIV) Infects Human Arterial Smooth Muscle Cells in Vivo and in Vitro: Implications for the Pathogenesis of HIV-Mediated Vascular Disease Am. J. Pathol., April 1, 2008; 172(4): 1100 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Delhaye, A. Gravot, D. Ayinde, F. Niedergang, M. Alizon, and A. Brelot Identification of a Postendocytic Sorting Sequence in CCR5 Mol. Pharmacol., December 1, 2007; 72(6): 1497 - 1507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. F. Neel, L. A. Lapierre, J. R. Goldenring, and A. Richmond RhoB plays an essential role in CXCR2 sorting decisions J. Cell Sci., May 1, 2007; 120(9): 1559 - 1571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Furci, F. Sironi, M. Tolazzi, L. Vassena, and P. Lusso {alpha}-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4 Blood, April 1, 2007; 109(7): 2928 - 2936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rey, A. Valenzuela-Fernandez, A. Urzainqui, M. Yanez-Mo, M. Perez-Martinez, P. Penela, F. Mayor Jr, and F. Sanchez-Madrid Myosin IIA is involved in the endocytosis of CXCR4 induced by SDF-1{alpha} J. Cell Sci., March 15, 2007; 120(6): 1126 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Masztalerz, I. S. Zeelenberg, Y. M. Wijnands, R. de Bruijn, A. M. Drager, H. Janssen, and E. Roos Synaptotagmin 3 deficiency in T cells impairs recycling of the chemokine receptor CXCR4 and thereby inhibits CXCL12 chemokine-induced migration J. Cell Sci., January 15, 2007; 120(2): 219 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Fox, P. Najarro, G. L. Smith, S. Struyf, P. Proost, and J. E. Pease Structure/Function Relationships of CCR8 Agonists and Antagonists: AMINO-TERMINAL EXTENSION OF CCL1 BY A SINGLE AMINO ACID GENERATES A PARTIAL AGONIST J. Biol. Chem., December 1, 2006; 281(48): 36652 - 36661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Otero, M. Groettrup, and D. F. Legler Opposite Fate of Endocytosed CCR7 and Its Ligands: Recycling versus Degradation J. Immunol., August 15, 2006; 177(4): 2314 - 2323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Michel, K. Ganter, S. Venzke, J. Bitzegeio, O. T. Fackler, and O. T. Keppler The Nef Protein of Human Immunodeficiency Virus Is a Broad-Spectrum Modulator of Chemokine Receptor Cell Surface Levels That Acts Independently of Classical Motifs for Receptor Endocytosis and G{alpha}i Signaling Mol. Biol. Cell, August 1, 2006; 17(8): 3578 - 3590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Deinhardt, O. Berninghausen, H. J. Willison, C. R. Hopkins, and G. Schiavo Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1 J. Cell Biol., July 31, 2006; 174(3): 459 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pastori, B. Weiser, C. Barassi, C. Uberti-Foppa, S. Ghezzi, R. Longhi, G. Calori, H. Burger, K. Kemal, G. Poli, et al. Long-lasting CCR5 internalization by antibodies in a subset of long-term nonprogressors: a possible protective effect against disease progression Blood, June 15, 2006; 107(12): 4825 - 4833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sbaa, J. DeWever, P. Martinive, C. Bouzin, F. Frerart, J.-L. Balligand, C. Dessy, and O. Feron Caveolin Plays a Central Role in Endothelial Progenitor Cell Mobilization and Homing in SDF-1-Driven Postischemic Vasculogenesis Circ. Res., May 12, 2006; 98(9): 1219 - 1227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ding, M. Li, J. Zhang, N. Li, Z. Xia, Y. Hu, S. Wang, and G.-H. Fan The 73-kDa Heat Shock Cognate Protein Is a CXCR4 Binding Protein that Regulates the Receptor Endocytosis and the Receptor-Mediated Chemotaxis Mol. Pharmacol., April 1, 2006; 69(4): 1269 - 1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Fitzsimons, U. A. Gompels, D. Verzijl, H. F. Vischer, C. Mattick, R. Leurs, and M. J. Smit Chemokine-Directed Trafficking of Receptor Stimulus to Different G Proteins: Selective Inducible and Constitutive Signaling by Human Herpesvirus 6-Encoded Chemokine Receptor U51 Mol. Pharmacol., March 1, 2006; 69(3): 888 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Woerner, N. M. Warrington, A. L. Kung, A. Perry, and J. B. Rubin Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies Cancer Res., December 15, 2005; 65(24): 11392 - 11399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. F. Hamdan, M. Audet, P. Garneau, J. Pelletier, and M. Bouvier High-Throughput Screening of G Protein-Coupled Receptor Antagonists Using a Bioluminescence Resonance Energy Transfer 1-Based {beta}-Arrestin2 Recruitment Assay J Biomol Screen, August 1, 2005; 10(5): 463 - 475. [Abstract] [PDF]
|
|
|
|
 |
|
 X. Jiao, N. Zhang, X. Xu, J. J. Oppenheim, and T. Jin Ligand-Induced Partitioning of Human CXCR1 Chemokine Receptors with Lipid Raft Microenvironments Facilitates G-Protein-Dependent Signaling Mol. Cell. Biol., July 1, 2005; 25(13): 5752 - 5762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Rose, K. Janvier, S. Chandrasekhar, R. P. Sekaly, J. S. Bonifacino, and S. Venkatesan CD4 Down-regulation by HIV-1 and Simian Immunodeficiency Virus (SIV) Nef Proteins Involves Both Internalization and Intracellular Retention Mechanisms J. Biol. Chem., March 4, 2005; 280(9): 7413 - 7426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Signoret, L. Hewlett, S. Wavre, A. Pelchen-Matthews, M. Oppermann, and M. Marsh Agonist-induced Endocytosis of CC Chemokine Receptor 5 Is Clathrin Dependent Mol. Biol. Cell, February 1, 2005; 16(2): 902 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. O. Barnard, S. Narayan, G. Dornadula, M. D. Miller, and J. A. T. Young Low pH Is Required for Avian Sarcoma and Leukosis Virus Env-Dependent Viral Penetration into the Cytosol and Not for Viral Uncoating J. Virol., October 1, 2004; 78(19): 10433 - 10441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Estall, B. Yusta, and D. J. Drucker Lipid Raft-dependent Glucagon-like Peptide-2 Receptor Trafficking Occurs Independently of Agonist-induced Desensitization Mol. Biol. Cell, August 1, 2004; 15(8): 3673 - 3687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sol-Foulon, C. Esnault, Y. Percherancier, F. Porrot, P. Metais-Cunha, F. Bachelerie, and O. Schwartz The Effects of HIV-1 Nef on CD4 Surface Expression and Viral Infectivity in Lymphoid Cells Are Independent of Rafts J. Biol. Chem., July 23, 2004; 279(30): 31398 - 31408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Rose, J. F. Foley, P. M. Murphy, and S. Venkatesan On the Mechanism and Significance of Ligand-induced Internalization of Human Neutrophil Chemokine Receptors CXCR1 and CXCR2 J. Biol. Chem., June 4, 2004; 279(23): 24372 - 24386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-H. Fan, L. A. Lapierre, J. R. Goldenring, J. Sai, and A. Richmond Rab11-Family Interacting Protein 2 and Myosin Vb Are Required for CXCR2 Recycling and Receptor-mediated Chemotaxis Mol. Biol. Cell, May 1, 2004; 15(5): 2456 - 2469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Weber, E. Blair, C. V. Simpson, M. O'Hara, P. E. Blackburn, A. Rot, G. J. Graham, and R. J.B. Nibbs The Chemokine Receptor D6 Constitutively Traffics to and from the Cell Surface to Internalize and Degrade Chemokines Mol. Biol. Cell, May 1, 2004; 15(5): 2492 - 2508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Gomez-Mouton, R. A. Lacalle, E. Mira, S. Jimenez-Baranda, D. F. Barber, A. C. Carrera, C. Martinez-A., and S. Manes Dynamic redistribution of raft domains as an organizing platform for signaling during cell chemotaxis J. Cell Biol., March 1, 2004; 164(5): 759 - 768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Nichols Caveosomes and endocytosis of lipid rafts J. Cell Sci., December 1, 2003; 116(23): 4707 - 4714. [Abstract] [Full Text] [PDF]
|
|
