title: Palmitoylation of the sphingosine 1-phosphate receptor S1P is involved in its signaling functions and internalization.
abstract: The lipid mediator sphingosine 1-phosphate (S1P) regulates several cellular processes through binding to its receptors (S1P(1)-S1P(5)), which are heterotrimeric G protein-coupled receptors. Here, we report that all S1P receptors are palmitoylated. In S1P(1), three Cys residues in the cytoplasmic tail are palmitoylated. We examined the roles of palmitoylation of S1P(1) using model cells in which wild-type S1P(1) or a non-palmitoylated mutant S1P(1) was overproduced. Compared with wild-type S1P(1), the non-palmitoylated S1P(1) exhibited binding affinity similar to the natural ligand S1P but lower to the synthetic ligand FTY720 phosphate (FTY720-P), the active form of the immunomodulator FTY720. However, downstream signaling of non-palmitoylated S1P(1) was similarly affected by S1P and FTY720-P stimulation. Moreover, upon stimulation with S1P, internalization of the mutant non-palmitoylated S1P(1) was retarded, compared with that of the wild-type protein. This effect was much more pronounced with FTY720-P stimulation. Similar differences were observed for the phosphorylation of S1P(1) and its mutant. These findings may provide insights into the molecular mechanisms of the pharmacological effects of FTY720. Finally, palmitoylation of wild-type S1P(1) increased upon treatment with S1P, suggesting that S1P(1) undergoes a palmitoylation/depalmitoylation cycle after stimulation by its ligands.
authors.affiliation: Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-choume, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohno
authors.forename: Ayako
authors.initials: A
authors.lastname: Ito
authors.forename: Ren
authors.initials: R
authors.lastname: Ogata
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hiraga
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Akio
authors.initials: A
authors.lastname: Kihara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D054878:Lipoylation; D008246:Lysophospholipids / Q000378:metabolism; D008969:Molecular Sequence Data; D049349:Receptors, Lysosphingolipid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D014162:Transfection
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine