Diverse glycosylation of MUC1 and MUC2: Potential significance in tumor immunity

Mucins are major epithelial luminal surface proteins and function as a phys ical and biological barrier protecting mucous epithelia, Diverse glycosylat ion of mucins potentially provides a basis for tissue-specific interaction with the milieu. When mucins are associated with malignant epithelial cells , they not only protect these cells from a host environment during metastat ic dissemination but also generate immunogenic epitopes which are used by t he host in the detection and immunological elimination of carcinoma cells p otentially depending upon their status of glycosylation. Diverse mucin stru ctures are generated by the combination of different core peptides, of whic h 10 have been reported so far, multiple types of UDP-GalNAc:polypeptide N- acetylgalactosaminyltransferases (pp-GalNAc-Ts), and the consequences of st epwise glycosylation events. For example, the mucin 1 (MUC1) associated wit h malignant cells was previously believed to exhibit unique features with a lower percentage of threonine and serine residues attached to N-acetylgala ctosamine and/ or without extension through core 2 structures. Some of MUC1 -specific monoclonal antibodies and cytotoxic lymphocytes recognize the pep tide sequences PDTR within the tandem repeat portion exposed by decreased d egree of glycosylation, The specific arrangement of N-acetylgalactosamine r esidues is shown to be generated by a combination of pp-GalNAc-Ts with diff erent specificities. The role of core 2 branching is somewhat confusing bec ause well-known carcinoma-associated carbohydrate epitopes such as sialyl-L e(X), sialyl-Le(a), Le(Y), and others are often expressed when O-glycans ar e extended through core 2 branching. The other series of well-known carcino ma-associated carbohydrate structures are truncated O-glycans, conventional ly called Tn and sialyl-Tn antigens. Interestingly, these are often found t o be aligned on core polypeptides, resulting in three or more consecutive t runcated O-glycans, MUC2 and other mucins, but not MUC1, have unique tandem repeats containing three or more consecutive serine or threonine residues, which potentially serve as a scaffold for trimeric Tn and sialyl-Tn epitop es, We recently found, using the MUGS tandem repeat, that trimeric Tn is a high-affinity receptor for a calcium-type lectin expressed on the surface o f histiocytic macrophages, The biosynthesis of trimeric Tn was strictly reg ulated by the acceptor specificity of pp-GalNAc-Ts. These results strongly suggest that variation in both glycan structures and distribution of glycan s on the core polypeptides give mucins unique and diverse biological functi ons that play essential roles in carcinoma-host and other cellular interact ions.