Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 33, Issue 12, Pages 3242-3254Publisher
WILEY
DOI: 10.1002/eji.200324189
Keywords
antigen processing; dendritic cells; MUC1 glycopeptides; cathepsin L; breast cancer vaccine
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Funding
- NCI NIH HHS [1R01 CA84106] Funding Source: Medline
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MUC1 is a glycoprotein overexpressed in breast cancer and other adenocarcinomas, and is known to elicit cellular and humoral immunity directed against unglycosylated peptide epitopes in the repeat domain. Based on immunological evidence that O-linked glycans on repeat peptides remain intact during processing by dendritic cells (DC), we used MUC1 as a model to address the question which role O-linked glycans play in this process. We were able to identify the sites of proteolysis in MUC1 repeats and the enzyme(s) involved, and elucidated the site-specific effects of O-glycosylation on MUC1 processing by human and mouse DC. Peptides generated by the cellular processing machinery from native mucin or (glyco)peptides suggest specific cleavage at Gly13-Ser14, His20-Gly1 and Thr3-Ser4 peptide bonds in the tandem repeat GVTSAPDTRPAPGSTAPPAH resulting in the initial formation of STA27 or GVT20 and SAP17 as the final product with intact O-glycosylation. Human cathepsin L and the corresponding mouse enzyme in low-density endosomes were identified in vitro to catalyze this site-specific MUC1 proteolysis. O-Glycosylation controls the processing by preventing proteolysis of the Thr3-Ser4 peptide bond if either amino acid is glycosylated, and is responsible for the inertness of tumor-associated MUC1 glycoforms to effective DC processing by masking this cleavage site.
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