The Tn Antigen—Structural Simplicity and Biological Complexity

Abstract

Glycoproteins in animal cells contain a variety of glycan structures that are added co- and/or posttranslationally to proteins. Of over 20 different types of sugar-amino acid linkages known, the two major types are N-glycans (Asn-linked) and O-glycans (Ser/Thr-linked). An abnormal mucin-type O-glycan whose expression is associated with cancer and several human disorders is the Tn antigen. It has a relatively simple structure composed of N-acetyl-D-galactosamine with a glycosidic α linkage to serine/threonine residues in glycoproteins (GalNAcα1-O-Ser/Thr), and was one of the first glycoconjugates to be chemically synthesized. The Tn antigen is normally modified by a specific galactosyltransferase (T-synthase) in the Golgi apparatus of cells. Expression of active T-synthase is uniquely dependent on the molecular chaperone Cosmc, which is encoded by a gene on the X chromosome. Expression of the Tn antigen can arise as a consequence of mutations in the genes for T-synthase or Cosmc, or genes affecting other steps of O-glycosylation pathways. Because of the association of the Tn antigen with disease, there is much interest in the development of Tn-based vaccines and other therapeutic approaches based on Tn expression.

Platelet biogenesis and functions require correct protein O-glycosylation

“…Tn syndrome, characterized by the expression of Tn antigen on a subpopulation of blood cells of all lineages (6), is caused by somatic mutation of Cosmc in hematopoietic stem cells and in some patients is accompanied by a mild bleeding diathesis. In some ways, the EHC Cosmc −/y mice partly represent Tn syndrome, although no evidence shows that endothelial cells are involved in Tn syndrome, and fewer hematopoietic cells, ranging from 20∼80%, are affected in different patients (11).…”

“…Glycoprotein O-glycans in all cells are extended by the key Golgi glycosyltransferase T-synthase (core 1 β3galactosyltransferase) that adds galactose to GalNAcα1-Ser/Thr (Tn antigen) to generate the core 1 O-glycan, Galβ1-3GalNAcα1-Ser/Thr, also known as the T antigen (6). Formation of active T-synthase dimers is unique in that it requires Cosmc (7,8), an essential and specific molecular chaperone in the endoplasmic reticulum (6, 9) encoded by X-linked Cosmc.…”

“…In cells lacking Cosmc, the active T-synthase is not expressed, the Tn antigen cannot be extended, and cells express the uncommon Tn antigen (10). Individuals with Tn syndrome, who have an acquired hematopoietic mutation in the X-linked Cosmc, demonstrate mosaicism in expression of the Tn antigen in a subpopulation of blood cells of all lineages (6,7,11) and can develop thrombocytopenia and anemia in association with altered platelet glycosylation (12). We recently reported that deletion of Cosmc in mice causes embryonic death at ∼embryonic day (E) 12.5 that is associated with hemorrhaging, similar to that observed for deletion of the T-synthase (10), a phenotype that could be a defect in either endothelial or hematopoietic lineages.…”

The Transmembrane Domain of the Molecular Chaperone Cosmc Directs Its Localization to the Endoplasmic Reticulum

“…The T-synthase is a Golgi enzyme that adds a galactose residue from the donor UDP-Gal to glycoproteins entering the Golgi that have the GalNAc␣1-Ser/Thr (Tn antigen) on mucin-type sequences to generate the core 1 disaccharide Gal␤1-3GalNAc␣1-Ser/Thr (T antigen) (29). Cosmc is a type II transmembrane protein (ϳ36 kDa) with a short cytoplasmic N-terminal domain, and a large ER lumenal domain that is not efficiently N-glycosylated and is the functional chaperone domain (24,25,28).…”

Glycans as Biomarkers: Status and Perspectives

“…As for O-glycans, mucin-type oligosaccharides are often truncated and express blood group associated antigens: T, sialyl T, Tn and sialyl Tn (11,19,(35)(36)(37)(38). Increased T and Tn antigens are found in bladder, breast, colon and gastric cancer, whereas elevated Tn is observed in liver metastasis, pancreatic and salivary gland cancer, and increased T antigen in lung cancer.…”