Immune regulation by the ST6Gal sialyltransferase

Abstract

The ST6Gal sialyltransferase controls production of the Sia␣2-6Gal␤1-4GlcNAc (Sia6LacNAc) trisaccharide, which is the ligand for the lectin CD22. Binding of CD22 to Sia6LacNAc is implicated in regulating lymphocyte adhesion and activation. We have investigated mice that lack ST6Gal and report that they are viable, yet exhibit hallmarks of severe immunosuppression unlike CD22-deficient mice. Notably, Sia6LacNAc-deficient mice display reduced serum IgM levels, impaired B cell proliferation in response to IgM and CD40 crosslinking, and attenuated antibody production to Tindependent and T-dependent antigens. Deficiency of ST6Gal was further found to alter phosphotyrosine accumulation during signal transduction from the B lymphocyte antigen receptor. These studies reveal that the ST6Gal sialyltransferase and corresponding production of the Sia6LacNAc oligosaccharide are essential in promoting B lymphocyte activation and immune function.Sialyltransferases are a family of glycosyltransferase enzymes that add sialic acid residues during oligosaccharide diversification (reviewed in ref. 1). Sialic acid addition occurs in the Golgi apparatus and generally terminates further oligosaccharide chain elongation. The outer position of sialic acid linkages places these residues in a location to provide key structural determinants in ligand formation for endogenous and pathogenic lectins. Three sialic acid linkage types commonly exist among vertebrates and the corresponding sialyltransferase genes have been previously isolated. The most abundant sialic acid linkage found among mammalian cell surface oligosaccharides is of the ␣2-3 variety and can be produced independently by four sialyltransferases that each, nonetheless, bear unique substrate preferences among glycolipids, asparagine (N)-linked glycans, and serine͞threonine (O)-linked glycans (2). Sialyltransferases have also been found to be developmentally regulated and differentially expressed among various cell types (1-6). For example, expression of ␣2-8 linked sialic acids is much less common than ␣2-3 linkages and appears restricted to a small subset of glycoproteins (7-10).␣2-6-linked sialic acids are also less abundant than ␣2-3-linked forms and are generated by at least four distinct gene products. However, the ST6Gal sialyltransferase appears solely responsible for producing the Sia␣2-6Gal␤1-4GlcNAc (Sia6LacNAc) terminus on various N glycans, and perhaps on some O glycans (1, 11). High levels of ST6Gal RNA have been found to preferentially accumulate in hematopoietic cells, as well as in the liver (3-5). Moreover, ST6Gal gene transcription is regulated by multiple promoters and altered by glucocorticoids and cytokines (12)(13)(14). Although the physiologic role of the ST6Gal sialyltransferase has not been defined previously by available genetic approaches, it has been shown to be unique in producing the ligand for the CD22 lectin molecule expressed on B lymphocytes.CD22 is a transmembrane glycoprotein lectin found exclusively on B lymphocytes and is known to p...

Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact

“…To investigate whether redistribution of CD22 to sites of cell contact is mediated by its ligand-binding domain, we used ST6GalI-null mice, which lack the CD22 ligand NeuGc␣2-6Gal (35). In contrast to the results with the WT mice ( Fig.…”

“…The activity of CD22 as a regulator of B cell signaling is modulated by the interaction of its extracellular ligand-binding domain with sialoside ligands on the same cell (cis) or adjacent cells (trans) (14,15,26,34,35,46). To date, few studies have investigated the dynamic interactions of cis and trans ligands and their relative roles in CD22 function.…”

“…Unless otherwise noted, antibodies used were obtained from Pharmingen, and the reagents were obtained from Sigma. C57BL͞6 mice were obtained from The Scripps Research Institute and ST6GalI-null and CD45-null mice were generated as described (35,36). Mice were male between the ages of 6 and 10 weeks.…”

“…2C). In these experiments, WT cells were differentiated from the ligand-deficient, ST6GalI-null cells by their ability to bind to the SNA lectin as described (35). CD22 on both WT and ST6GalI-null B cells was found to redistribute to sites of cell contact with WT lymphocytes.…”

Diseases of glycosylation beyond classical congenital disorders of glycosylation

“…The addition of Sia is catalyzed by a family of 20 sialyltransferase enzymes, which transfer Sia via 2-3, 2-6 and 2-8 linkages to various glycan acceptors [46]. The disruption of sialyltransferase genes in mice often results in immune and hematologic phenotypes [47][48][49]. Very recently, mutations in the 2-3 sialyltransferase gene ST3GAL3 (OMIM ID: 606494) have been associated with nonsyndromic mental retardation [50].…”