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PMID: 20364150 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Production of an antigenic peptide by insulin-degrading enzyme.

Nature immunology ·Vol. 11 ·No. 5 ·2010-05-00 ·Pages 449-54

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

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.

MeSH Terms
Antibodies, Blocking/pharmacology Antigen Presentation/drug effects,genetics Antigens, Neoplasm/immunology,metabolism Cell Fractionation Cell Line, Tumor Chromatography, High Pressure Liquid Clone Cells Cytosol Glycopeptides/pharmacology HLA-A1 Antigen/metabolism Humans Insulysin/genetics,immunology,metabolism Interferon-gamma/metabolism Mass Spectrometry Metalloendopeptidases/antagonists & inhibitors Neoplasm Proteins/immunology,metabolism Oligopeptides/pharmacology Peptide Fragments/immunology,metabolism Phenanthrolines/pharmacology Proteasome Inhibitors RNA, Small Interfering/genetics T-Lymphocytes, Cytotoxic/immunology,metabolism,pathology
Chemicals
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
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Parmentier Nicolas
Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium.
Stroobant Vincent
Colau Didier
de Diesbach Philippe
Morel Sandra
Chapiro Jacques
van Endert Peter
Van den Eynde Benoît J
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1862
Published
2010-05-00
Epub
2010-00-04
Pages
449-54
Language
English
Region
United States
NLM ID
100941354
Subset
IM
External Links
PubMed source DOI: 10.1038/ni.1862 View journal details
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