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The proteasome produces MHC class I-restricted antigenic peptides carrying N-terminal extensions, which are trimmed by other peptidases in the cytosol or within the endoplasmic reticulum. In this study, we show that the N-terminal editing of an antigenic peptide with a predicted low TAP affinity can occur in the cytosol. Using proteomics, we identified two cytosolic peptidases, tripeptidyl peptidase II and puromycin-sensitive aminopeptidase, that trimmed the N-terminal extensions of the precursors produced by the proteasome, and led to a transient enrichment of the final antigenic peptide. These peptidases acted either sequentially or redundantly, depending on the extension remaining at the N terminus of the peptides released from the proteasome. Inhibition of these peptidases abolished the CTL-mediated recognition of Ag-expressing cells. Although we observed some proteolytic activity in fractions enriched in endoplasmic reticulum, it could not compensate for the loss of tripeptidyl peptidase II/puromycin-sensitive aminopeptidase activities.


Journal article


J Immunol

Publication Date





4161 - 4171


Acetylcysteine, Amino Acid Chloromethyl Ketones, Amino Acid Sequence, Aminopeptidases, Antigen Presentation, Cell Line, Cytosol, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Enzyme Inhibitors, HLA-B Antigens, HLA-B51 Antigen, Humans, Hydrolysis, Molecular Sequence Data, Oligopeptides, Peptide Fragments, Proline, Protein Precursors, Protein Processing, Post-Translational, Puromycin, Serine Endopeptidases, T-Lymphocytes, Cytotoxic, Transfection, Tumor Cells, Cultured