Production of an antigenic peptide by insulin-degrading enzyme.

Parmentier N., Stroobant V., Colau D., de Diesbach P., Morel S., Chapiro J., van Endert P., Van den Eynde BJ.

Most antigenic peptides presented by major histocompatibility complex (MHC) class I molecules are produced by the proteasome. Here we show that a proteasome-independent peptide derived from the human tumor protein MAGE-A3 is produced directly by insulin-degrading enzyme (IDE), a cytosolic metallopeptidase. Cytotoxic T lymphocyte recognition of tumor cells was reduced after metallopeptidase inhibition or IDE silencing. Separate inhibition of the metallopeptidase and the proteasome impaired degradation of MAGE-A3 proteins, and simultaneous inhibition of both further stabilized MAGE-A3 proteins. These results suggest that MAGE-A3 proteins are degraded along two parallel pathways that involve either the proteasome or IDE and produce different sets of antigenic peptides presented by MHC class I molecules.

DOI

10.1038/ni.1862

Type

Journal article

Journal

Nat Immunol

Publication Date

05/2010

Volume

11

Pages

449 - 454

Keywords

Antibodies, Blocking, Antigen Presentation, Antigens, Neoplasm, Cell Fractionation, Cell Line, Tumor, Chromatography, High Pressure Liquid, Clone Cells, Cytosol, Glycopeptides, HLA-A1 Antigen, Humans, Insulysin, Interferon-gamma, Mass Spectrometry, Metalloendopeptidases, Neoplasm Proteins, Oligopeptides, Peptide Fragments, Phenanthrolines, Proteasome Inhibitors, RNA, Small Interfering, T-Lymphocytes, Cytotoxic

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