Glycosyltransferase Function in Core 2-Type Protein O Glycosylation

Abstract

Three glycosyltransferases have been identified in mammals that can initiate core 2 protein O glycosylation. Core 2 O-glycans are abundant among glycoproteins but, to date, few functions for these structures have been identified. To investigate the biological roles of core 2 O-glycans, we produced and characterized mice deficient in one or more of the three known glycosyltransferases that generate core 2 O-glycans (C2GnT1, C2GnT2, and C2GnT3). A role for C2GnT1 in selectin ligand formation has been described. We now report that C2GnT2 deficiency impaired the mucosal barrier and increased susceptibility to colitis. C2GnT2 deficiency also reduced immunoglobulin abundance and resulted in the loss of all core 4 O-glycan biosynthetic activity. In contrast, the absence of C2GnT3 altered behavior linked to reduced thyroxine levels in circulation. Remarkably, elimination of all three C2GnTs was permissive of viability and fertility. Core 2 O-glycan structures were reduced among tissues from individual C2GnT deficiencies and completely absent from triply deficient mice. C2GnT deficiency also induced alterations in Ibranching, core 1 O-glycan formation, and O mannosylation. Although the absence of C2GnT and C4GnT activities is tolerable in vivo, core 2 O glycosylation exerts a significant influence on O-glycan biosynthesis and is important in multiple physiological processes.

Mucin-bacterial interactions in the human oral cavity and digestive tract

“…When in mice the O-glycosylation is altered, by knocking out either a specific core 3 type glycosyltransferase or a set of three core 2 type glycosyltransferase, the mice are rendered more susceptible to development of colitis. 44,45 A similar effect is caused by knocking out the intestinal sulfate transporter, which leads to under-sulfated intestinal mucin, which also increases the sensitivity to small intestinal infections and the development of experimental colitis in these mice. 46 In diverse intestinal infection models in the mouse it was clearly demonstrated that mucin production as well as mucin structure was influenced by the presence of pathogens.…”

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

“…Because core 2 O-linked glycosylation is critical for the formation of functional selectin ligands, we conducted a longitudinal analysis of core 2 O-glycan expression on antigen-specific CD8 + T cells following viral infection by transferring a physiologic number of naive Thy1.1 + P14 TCR-tg CD8 + T cells (specific for the lymphocytic choriomeningitis virus [LCMV] epitope GP [33][34][35][36][37][38][39][40][41] into Thy1.2 + B6 recipients, followed by infection with LCMV Armstrong. To detect changes in expression of core 2 O-glycans, we used the monoclonal antibody 1B11, which identifies a modified isoform of CD43 that is generated following core 2 O-linked glycosylation of the protein (34)(35)(36).…”

Genetic control of susceptibility to carcinogen-induced colorectal cancer in mice: TheCcs3andCcs5loci regulate different aspects of tumorigenesis

“…Nineteen weeks glucosaminyl (N-acetyl) transferase 3 (Gcnt3) participates in the biosynthesis of mucin-type glycans and Gcnt3 mutant mice display increased susceptibility to DSS-induced colitis. 53 Within the Ccs5 interval, several genes belong to the Bcl-2-related protein family involved in regulation of cell survival (Bcl2a1a, Bcl2a1b, Bcl2a1d, Bcl2l10, Bnip2). The single human BCL2A1 homolog BFL-1 is expressed at high levels in gastric and colon cancers, 54 and appears to function as a direct target of Nfκb for suppression of TNFα-induced apoptosis.…”