Research Highlights

Cosmc: A chaperone changes surface glycan immunogenicity

The characterization of immunogenic cancer glycans and the identification of reactive antibodies are crucial for understanding the glycobiology of disease. Altered expression levels of glycosyltransferases are generally thought to be the cause for the formation of immunogenic cancer glycans. The chaperone Cosmc has been shown to be required for the activity of C13GALT, an enzyme which elongates initial N-acetylgalactosamine glycosylation of serine or threonine by transferring galactose. Whether Cosmc is involved in the origin of antigenic glycan structures in cancer cells has not been addressed until now.

Andrea Schietinger and colleagues investigated the effects of expressing the tumor-specific transmembrane glycoprotein OTS8 in murine fibrosarcoma cells. OTS8 is overexpressed in various tumors, yet the authors revealed that only OTS8 expressed in the Ag104A cell line reacted with a syngeneic, monoclonal antibody, 237 mAb

After treatment of Ag104A-OTS8 with a reagent that specifically destroys carbohydrate structures, its antibody reactivity ceased. Schietinger and colleagues then overexpressed various histidine-tagged regions of the extracellular domain of OTS8 in Ag104A cells to single out amino acid residues carrying glycans. By mutating putative glycosylation sites, a threonine residue was identified to carry a single N-Acetylgalactosamine, known as Tn-antigen. This sugar structure in combination with a 10-amino acid wild-type peptide sequence was found to constitute the tumor-specific antigen.

It is already known that in non-tumor (e.g., Jurkat) cells mutation of Cosmc leads to loss of C13GALT activity and Tn-antigen expression. In line with this observation, the authors found that a deletion in the Ag104A-Cosmc cDNA caused the expression of a non-functional C13GALT. A broad range of surface proteins was found to carry the Tn antigen, since an alteration of glucosyltransferase function can result in changed glycan structures of several surface proteins.

The findings of Schietinger and colleagues demonstrate that a tumor antigen can arise from changes in posttranslational modifications alone, and that they do not require a mutation in the gene coding the carrier protein itself. Second, cancer-related glycan changes can be caused not only by changes in the transcription level of glycosyltransferases, but also by other proteins that modulate transferase activity.

Author: Mirko von Elstermann