Production of an antigenic peptide by insulin-degrading enzyme.
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.
Parmentier
Nicolas
N
Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium.
Stroobant
Vincent
V
Colau
Didier
D
de Diesbach
Philippe
P
Morel
Sandra
S
Chapiro
Jacques
J
van Endert
Peter
P
Van den Eynde
Benoît J
BJ
D019138:Antibodies, Blocking / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002999:Clone Cells; D003600:Cytosol; D006020:Glycopeptides / Q000494:pharmacology; D015788:HLA-A1 Antigen / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D013058:Mass Spectrometry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D019138:Antibodies, Blocking; D000951:Antigens, Neoplasm; D006020:Glycopeptides; D015788:HLA-A1 Antigen; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D010618:Phenanthrolines; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; D007339:Insulysin; C008890:phosphoramidon; C078846:epoxomicin