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Molecular and Cellular Biology, July 2006, p. 4970-4981, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.00308-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

ST6Gal-I Restrains CD22-Dependent Antigen Receptor Endocytosis and Shp-1 Recruitment in Normal and Pathogenic Immune Signaling

Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, 9500 Gilman Drive MC0625, University of California—San Diego, La Jolla, California 92093,¹ Departments of Molecular Biology and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037²

Received 18 February 2006/ Returned for modification 5 April 2006/ Accepted 19 April 2006

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 Ig/ß, Syk, and phospholipase C-2 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.

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