AIDSWEEKLY Plus; Monday, October 13, 2003
Staff Medical Writers

"Desensitization of the chemokine receptors, a large class of G protein-coupled receptors, is mediated in part by agonist-driven receptor endocytosis," scientists in the United States explained. "However, the exact pathways have not been fully defined."

In a recent study, S. Venkatesan and colleagues at the National Institute of Allergy and Infectious Diseases found 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," the investigators wrote in the journal Molecular Biology of the Cell. "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."

Test results also revealed that "the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts," according to the report. "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," published data indicated.

"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," the researchers concluded. "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."

Venkatesan and coauthors published their study in Molecular Biology of the Cell (Distinct mechanisms of agonist-induced endocytosis for human chemokine receptors CCR5 and CXCR4. Mol Biol Cell. 2003 Aug;14(8):3305-24..

For more information, contact S. Venkatesan, NIAID, Molecular Biology Laboratory, National Institutes of Health, Bethesda, MD 20892, USA.

Publisher contact information for the journal Molecular Biology of the Cell is: American Society for Cell Biology, 8120 Woodmont Avenue, Ste. 750, Bethesda, MD 20814-2755, USA.

The information in this article comes under the major subject areas of AIDS & HIV and Receptor Studies.

This article was prepared by AIDS Weekly editors from staff and other reports.

Reference

Venkatesan S, Rose JJ, Lodge R, et al. "Distinct mechanisms of agonist-induced endocytosis for human chemokine receptors CCR5 and CXCR4", Mol Biol Cell. 2003 Aug;14(8):3305-24.

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