PeptideAtlasGarris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, Moon BS, Axtell RC, Ho PP, Steinberg GK, Lewis DB, Sobel RA, Han DK, Steinman L, Snyder MP, Hla T, Han MHTPP'https://db.systemsbiology.net/sbeams/cgi/PeptideAtlas/ManageTable.cgi?TABLE_NAME=AT_sample&sample_id=6418'linfeng.wu@stanford.eduBrainPeptideAtlasProteomicsLTQ Orbitrap VelosHomo Sapiens (human)Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.Garris Christopher S CS, Wu Linfeng L, Acharya Swati S, Arac Ahmet A, Blaho Victoria A VA, Huang Yingxiang Y, Moon Byoung San BS, Axtell Robert C RC, Ho Peggy P PP, Steinberg Gary K GK, Lewis David B DB, Sobel Raymond A RA, Han David K DK, Steinman Lawrence L, Snyder Michael P MP, Hla Timothy T, Han May H 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