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.
Medical Research Council Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, Gower Street, London WC1E 6BT, UK.
N
N
Signoret
M M
MM
Rosenkilde
P J
PJ
Klasse
T W
TW
Schwartz
M H
MH
Malim
J A
JA
Hoxie
M
M
Marsh
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