Type 1 sphingosine 1-phosphate G protein-coupled receptor signaling of lymphocyte functions requires sulfation of its extracellular amino-terminal tyrosines.
The type 1 sphingosine 1-phosphate (S1P) G protein-coupled receptor (S1P1) transduces signals from S1P that mediate thymocyte emigration, T cell transmigration of lymph nodes, and T cell chemotaxis in tissues. Alterations in expression of functional S1P1 receptors by lymphocytes are the major mechanisms controlling their responses to S1P and were thought to be solely a consequence of the balance between surface down-regulation and insertion. However, results now show that lack of sulfation of tyrosines 19 and 22 of the extracellular N terminus of S1P1 diminishes high-affinity S1P binding and decreases S1P signaling of T cell migration and other functions. Non-sulfatable mutant (Y19,22F)S1P1 endows T cells with lower-affinity binding of [32P]S1P than wild-type S1P1 and transduces lesser effects of S1P on chemotaxis, chemokine-elicited chemotaxis, and T cell receptor-mediated proliferation and cytokine generation. Inhibition of S1P1 tyrosine sulfation or sulfatase removal of S1P1 sulfate in mouse CD4 T cells suppresses immune functional effects of S1P. Tyrosine sulfation of S1P1 may be a major controller of S1P effects on T cell traffic.
Fieger
Claudia B
CB
Department of Anatomy, University of California, San Francisco, California 94143-0711, USA.
Huang
Mei-Chuan
MC
Van Brocklyn
James R
JR
Goetzl
Edward J
EJ
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008207:Lymphatic Metastasis; D008214:Lymphocytes / Q000166:cytology*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D049312:Receptors, Lysophospholipid / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry*
D016207:Cytokines; D008055:Lipids; D008246:Lysophospholipids; D049312:Receptors, Lysophospholipid; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D014443:Tyrosine; D007371:Interferon-gamma; D013110:Sphingosine