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The nonclassical major histocompatibility complex class I molecule HLA-E acts as a ligand for CD94/NKG2 receptors on the surface of natural killer cells and a subset of T cells. HLA-E presents closely related nonameric peptide epitopes derived from the highly conserved signal sequences of classical major histocompatibility complex class I molecules as well as HLA-G. Their generation requires cleavage of the signal sequence by signal peptidase followed by the intramembrane-cleaving aspartic protease, signal peptide peptidase. In this study, we have assessed the subsequent proteolytic requirements leading to generation of the nonameric HLA-E peptide epitopes. We show that proteasome activity is required for further processing of the peptide generated by signal peptide peptidase. This constitutes the first example of capture of a naturally derived short peptide by the proteasome, producing a class I peptide ligand.

Original publication




Journal article


J Biol Chem

Publication Date





33747 - 33752


Acetylcysteine, Acids, Alleles, Amino Acid Sequence, Aspartic Acid Endopeptidases, Cell Line, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Cytosol, Dose-Response Relationship, Drug, Epitopes, Flow Cytometry, HLA Antigens, HLA-G Antigens, Histocompatibility Antigens Class I, Humans, Ligands, Membrane Proteins, Molecular Sequence Data, Multienzyme Complexes, Oligopeptides, Peptide Hydrolases, Peptides, Plasmids, Proteasome Endopeptidase Complex, Protein Biosynthesis, Protein Structure, Tertiary, Serine Endopeptidases, Transcription, Genetic, Transfection