The Cosmc connection to the Tn antigen in cancer

Abstract

The Tn antigen is a tumor-associated carbohydrate antigen that is not normally expressed in peripheral tissues or blood cells. Expression of this antigen, which is found in a majority of human carcinomas of all types, arises from a blockage in the normal O-glycosylation pathway in which glycans are extended from the common precursor GalNAcα1-O-Ser/Thr (Tn antigen). This precursor is generated in the Golgi apparatus on newly synthesized glycoproteins by a family of polypeptide α-N-acetylgalactosaminyltransferases (ppGalNAcTs) and then extended to the common core 1 O-glycan Galβ1-3GalNAcα1-O-Ser/Thr (T antigen) by a single enzyme termed the T-synthase (core 1 β3-galactosyltransferase or C1GalT). Formation of the active form of the T-synthase requires a unique molecular chaperone termed Cosmc, encoded by Cosmc on the X-chromosome (Xq24 in humans, Xc3 in mice). Cosmc resides in the endoplasmic reticulum (ER) and prevents misfolding, aggregation, and proteasome-dependent degradation of newly synthesized T-synthase. Loss of expression of active T-synthase or Cosmc can lead to expression of the Tn antigen, along with its sialylated version Sialyl Tn antigen as observed in several cancers. Both genetic and epigenetic pathways, in addition to potential metabolic regulation, can result in abnormal expression of the Tn antigen. Engineered expression of the Tn antigen by disruption of either C1GalT (T-syn) or Cosmc in mice is associated with a tremendous range of pathologies and engineered expression of the Tn antigen in mouse embryos leads to embryonic death. Studies indicate that many membrane glycoproteins expressing the Tn antigen and/or truncated O-glycans may be dysfunctional, due to degradation and/or misfolding. Thus, expression of normal O-glycans is associated with health and homeostasis whereas truncation of O-glycans, e.g. the Tn and/or Sialyl Tn antigens is associated with cancer and other pathologies.

Keywords: Cosmc; T-synthase; Tn antigen; cancer.

Fig. 1

O-glycan biosynthetic pathways. Glycoprotein biosynthesis begins in the ER where N-glycans are added co-translationally, but O-g-lycosylation is initiated normally in the Golgi apparatus, where the T-synthase adds galactose from UDP-Gal to the common precursor GalNAcα1-Ser/Thr (Tn antigen) to generate a core 1 O-glycan Galβ1-3GalNAcα1-Ser/Thr. This is then extended by addition of other sugars to generate the normal O-glycans. In the absence of function of the molecular chaperone Cosmc, which is required for formation of active T-synthase, glycoproteins express the Tn antigen. This can lead to glycoprotein misfolding, abnormal oligomerization, instability, proteolysis, loss-of-function, and abnormal recognition by glycan-binding proteins (GBPs). (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/CBM-130375)

Fig. 2

Structures of short O-glycans. The structures of the Tn, STn and core 3 O-glycans are shown on the left. In some glycoproteins clusters of O-glycans shown here as the Tn antigen may occur on adjacent or closely spaced Ser/Thr residues, as shown on the right. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/CBM-130375)

Fig. 3

Cosmc is a chaperone for the T-synthase. Working model of the mechanism of Cosmc function in the expression of the T-synthase and postulated expression of Tn/STn antigens associated with dysfunctional Cosmc. Cosmc is an ER-localized chaperone, which may exist as an oligomeric complex. Cosmc directly interacts with newly synthesized non-native T-synthase, facilitating folding of the T-synthase (left). In the absence of functional Cosmc, T-synthase aggregates into non-productive aggregates (right) and associates with other chaperones, e.g. Grp78, and is subsequently ubiquitinylated and degraded by the 26S proteasome system. The active dimeric form of the T-synthase exits to the Golgi apparatus. Normal expression of Cosmc and T-synthase leads to normal O-glycan expression and complex structures on plasma membrane glycoproteins, whereas lack of Cosmc and T-synthase leads to expression of Tn and Sialyl Tn antigen. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/CBM-130375)

Fig. 4

Altered O-glycosylation of proteins contributes to altered activities. Glycoproteins expressing the abnormal O-glycan the Tn antigen may have altered structure and stability, and may not oligomerize properly nor be expressed stably on the membrane. Abnormal expression of the O-glycan Tn antigen in glycoproteins, instead of normal, extended O-glycans, can lead to altered glycoprotein expression and function. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/CBM-130375)