Production of an antigenic peptide by insulin-degrading enzyme

Nicolas Parmentier; Vincent Stroobant; Didier Colau; Philippe de Diesbach; Sandra Morel; Jacques Chapiro; Peter van Endert; Benoît J Van den Eynde

doi:10.1038/ni.1862

Production of an antigenic peptide by insulin-degrading enzyme

Nat Immunol. 2010 May;11(5):449-54. doi: 10.1038/ni.1862. Epub 2010 Apr 4.

Authors

Nicolas Parmentier¹, Vincent Stroobant, Didier Colau, Philippe de Diesbach, Sandra Morel, Jacques Chapiro, Peter van Endert, Benoît J Van den Eynde

Affiliation

¹ Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium.

PMID: 20364150
DOI: 10.1038/ni.1862

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

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Blocking / pharmacology
Antigen Presentation* / drug effects
Antigen Presentation* / genetics
Antigens, Neoplasm / immunology
Antigens, Neoplasm / metabolism*
Cell Fractionation
Cell Line, Tumor
Chromatography, High Pressure Liquid
Clone Cells
Cytosol
Glycopeptides / pharmacology
HLA-A1 Antigen / metabolism
Humans
Insulysin / genetics
Insulysin / immunology
Insulysin / metabolism*
Interferon-gamma / metabolism
Mass Spectrometry
Metalloendopeptidases / antagonists & inhibitors
Neoplasm Proteins / immunology
Neoplasm Proteins / metabolism*
Oligopeptides / pharmacology
Peptide Fragments / immunology
Peptide Fragments / metabolism*
Phenanthrolines / pharmacology
Proteasome Inhibitors
RNA, Small Interfering / genetics
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism*
T-Lymphocytes, Cytotoxic / pathology

Substances

Antibodies, Blocking
Antigens, Neoplasm
Glycopeptides
HLA-A1 Antigen
MAGEA3 protein, human
Neoplasm Proteins
Oligopeptides
Peptide Fragments
Phenanthrolines
Proteasome Inhibitors
RNA, Small Interfering
Interferon-gamma
Metalloendopeptidases
thimet oligopeptidase
Insulysin
phosphoramidon
epoxomicin