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Yusuke Ohno¹, Ayako Ito², Ren Ogata¹, Yuki Hiraga², Yasuyuki Igarashi³ and Akio Kihara^1,*

¹ Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-choume, Kita-ku, Sapporo 060-0812, Japan
² Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-choume, Kita-ku, Sapporo 060-0812, Japan
³ Laboratory of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Sciences, Hokkaido University, Kita 21-jo, Nishi 11-choume, Kita-ku, Sapporo 001-0021, Japan

The lipid mediator sphingosine 1-phosphate (S1P) regulates several cellular processes through binding to its receptors (S1P₁–S1P₅), which are heterotrimeric G protein-coupled receptors. Here, we report that all S1P receptors are palmitoylated. In S1P₁, three Cys residues in the cytoplasmic tail are palmitoylated. We examined the roles of palmitoylation of S1P₁ using model cells in which wild-type S1P₁ or a non-palmitoylated mutant S1P₁ was overproduced. Compared with wild-type S1P₁, the non-palmitoylated S1P₁ 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 S1P₁ was similarly affected by S1P and FTY720-P stimulation. Moreover, upon stimulation with S1P, internalization of the mutant non-palmitoylated S1P₁ 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 S1P₁ and its mutant. These findings may provide insights into the molecular mechanisms of the pharmacological effects of FTY720. Finally, palmitoylation of wild-type S1P₁ increased upon treatment with S1P, suggesting that S1P₁ undergoes a palmitoylation/depalmitoylation cycle after stimulation by its ligands.

These authors contributed equally to this work.

^* kihara{at}pharm.hokudai.ac.jp