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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{dagger}

Prabhjit K. Grewal,1 Mark Boton,1 Kevin Ramirez,1 Brian E. Collins,2 Akira Saito,1 Ryan S. Green,1 Kazuaki Ohtsubo,1 Daniel Chui,1 and Jamey D. Marth1*

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{alpha}/ß, Syk, and phospholipase C-{gamma}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.

* Corresponding author. Mailing address: Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute, 9500 Gilman Drive MC0625, University of California—San Diego, La Jolla, CA 92093. Phone: (858) 534-6526. Fax: (858) 534-6724. E-mail: jmarth{at}ucsd.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

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.



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