ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling.
The ST6Gal-I sialyltransferase produces Siglec ligands for the B-cell-specific CD22 lectin and sustains humoral immune responses. Using multiple experimental approaches to elucidate the mechanisms involved, we report that ST6Gal-I deficiency induces immunoglobulin M (IgM) antigen receptor endocytosis in the absence of immune stimulation. This coincides with increased antigen receptor colocalization with CD22 in both clathrin-deficient and clathrin-enriched membrane microdomains concurrent with diminished tyrosine phosphorylation of Igalpha/beta, Syk, and phospholipase C-gamma2 upon immune activation. Codeficiency with CD22 restores IgM antigen receptor half-life at the cell surface in addition to reversing alterations in membrane trafficking and immune signaling. Diminished immune responses due to ST6Gal-I deficiency further correlate with constitutive recruitment of Shp-1 to CD22 in unstimulated B cells independent of Lyn tyrosine kinase activity and prevent autoimmune disease pathogenesis in the Lyn-deficient model of systemic lupus erythematosus, resulting in a significant extension of life span. Protein glycosylation by ST6Gal-I restricts access of antigen receptors and Shp-1 to CD22 and operates by a CD22-dependent mechanism that decreases the basal rate of IgM antigen receptor endocytosis in altering the threshold of B-cell immune activation.
Grewal
Prabhjit K
PK
Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, 9500 Gilman Drive MC0625, University of California-San Diego, La Jolla, CA 92093, USA.
Boton
Mark
M
Ramirez
Kevin
K
Collins
Brian E
BE
Saito
Akira
A
Green
Ryan S
RS
Ohtsubo
Kazuaki
K
Chui
Daniel
D
Marth
Jamey D
JD
D000818:Animals; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism; D006031:Glycosylation; D007109:Immunity / Q000235:genetics; D007075:Immunoglobulin M / Q000032:analysis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000737:chemistry; D051379:Mice; D008817:Mice, Mutant Strains; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000032:analysis / Q000378:metabolism; D011961:Receptors, Fc / Q000032:analysis / Q000378:metabolism*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D006023:Glycoproteins; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D051918:Sialic Acid Binding Ig-like Lectin 2; C035311:immunoglobulin M receptor; D014443:Tyrosine; D012799:Sialyltransferases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D019158:N-Acetylneuraminic Acid; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase