Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Blocking / pharmacology
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Antigen Presentation* / drug effects
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Antigen Presentation* / genetics
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / metabolism*
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Cell Fractionation
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Cell Line, Tumor
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Chromatography, High Pressure Liquid
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Clone Cells
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Cytosol
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Glycopeptides / pharmacology
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HLA-A1 Antigen / metabolism
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Humans
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Insulysin / genetics
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Insulysin / immunology
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Insulysin / metabolism*
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Interferon-gamma / metabolism
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Mass Spectrometry
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Metalloendopeptidases / antagonists & inhibitors
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Neoplasm Proteins / immunology
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Neoplasm Proteins / metabolism*
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Oligopeptides / pharmacology
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Peptide Fragments / immunology
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Peptide Fragments / metabolism*
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Phenanthrolines / pharmacology
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Proteasome Inhibitors
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RNA, Small Interfering / genetics
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism*
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T-Lymphocytes, Cytotoxic / pathology
Substances
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Antibodies, Blocking
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Antigens, Neoplasm
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Glycopeptides
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HLA-A1 Antigen
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MAGEA3 protein, human
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Neoplasm Proteins
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Oligopeptides
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Peptide Fragments
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Phenanthrolines
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Proteasome Inhibitors
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RNA, Small Interfering
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Interferon-gamma
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Metalloendopeptidases
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thimet oligopeptidase
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Insulysin
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phosphoramidon
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epoxomicin