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.