Differential regulation of CXCR4 and CCR5 endocytosis.
The chemokine receptors CCR5 and CXCR4 are major co-receptors/receptors for the CD4-dependent and CD4-independent entry of human and simian immunodeficiency viruses. The chemokines that bind and activate these receptors can inhibit the entry of viruses that use the respective co-receptor molecules. Chemokine-induced co-receptor internalisation is a significant component of the mechanism through which chemokines inhibit virus entry. CXCR4 internalisation is induced by the CXCR4 ligand stromal cell derived factor-1 (SDF-1), phorbol esters and, in T cells, cellular activation. Here we show that CXCR4 endocytosis can be mediated through either one of two distinct internalisation signals. A COOH-terminal serine rich domain is required for ligand- but not phorbol ester- induced CXCR4 internalisation. However, a Ser/IleLeu motif, similar to that required for the endocytosis of CD4 and the T cell receptor/CD3 complex, is required for phorbol ester-induced, but not ligand-induced, CXCR4 endocytosis. By contrast, CCR5 internalisation is induced by the beta-chemokine RANTES but not by phorbol esters. CCR5 lacks the Ser/IleLeu sequence required for phorbol ester-induced uptake of CXCR4. Together these results indicate that distinct mechanisms can regulate CXCR4 and CCR5 endocytosis and trafficking.
Signoret
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Medical Research Council Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, Gower Street, London WC1E 6BT, UK.
Rosenkilde
M M
MM
Klasse
P J
PJ
Schwartz
T W
TW
Malim
M H
MH
Hoxie
J A
JA
Marsh
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D006678:HIV / Q000472:pathogenicity; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019713:Receptors, CCR5 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D013755:Tetradecanoylphorbol Acetate