Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / chemistry
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Endocytosis* / genetics
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Glycoproteins / metabolism
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Glycosylation
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Immunity / genetics
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Immunoglobulin M / analysis
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Immunoglobulin M / immunology
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Intracellular Signaling Peptides and Proteins / analysis
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology
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Lymphocyte Activation
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Membrane Microdomains / chemistry
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Mice
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Mice, Mutant Strains
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N-Acetylneuraminic Acid / metabolism
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / analysis
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Protein Tyrosine Phosphatases / metabolism*
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Receptors, Antigen, B-Cell / analysis
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Receptors, Antigen, B-Cell / metabolism
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Receptors, Fc / analysis
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Receptors, Fc / metabolism*
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Sialic Acid Binding Ig-like Lectin 2 / analysis
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Sialic Acid Binding Ig-like Lectin 2 / genetics
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Sialic Acid Binding Ig-like Lectin 2 / metabolism*
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Sialyltransferases / genetics
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Sialyltransferases / metabolism*
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Signal Transduction
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Tyrosine / metabolism
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beta-D-Galactoside alpha 2-6-Sialyltransferase
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
Substances
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Glycoproteins
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Immunoglobulin M
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Intracellular Signaling Peptides and Proteins
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Receptors, Antigen, B-Cell
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Receptors, Fc
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Sialic Acid Binding Ig-like Lectin 2
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immunoglobulin M receptor
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Tyrosine
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Sialyltransferases
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lyn protein-tyrosine kinase
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src-Family Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn6 protein, mouse
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N-Acetylneuraminic Acid
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beta-D-Galactoside alpha 2-6-Sialyltransferase