title: Requirement of the proteasome for the trimming of signal peptide-derived epitopes presented by the nonclassical major histocompatibility complex class I molecule HLA-E.
abstract: 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.
authors.affiliation: Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
authors.forename: Felicity A
authors.initials: FA
authors.lastname: Bland
authors.forename: Marius K
authors.initials: MK
authors.lastname: Lemberg
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: Bruno
authors.initials: B
authors.lastname: Martoglio
authors.forename: Veronique M
authors.initials: VM
authors.lastname: Braud
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000143:Acids / Q000494:pharmacology; D000483:Alleles; D000595:Amino Acid Sequence; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D006680:HLA Antigens / Q000737:chemistry*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry; D014158:Transcription, Genetic; D014162:Transfection; D000097625:HLA-E Antigens
chemical_list: D000111:Acetylcysteine; D000143:Acids; D016282:Aspartic Acid Endopeptidases; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D000939:Epitopes; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D010447:Peptide Hydrolases; D010455:Peptides; D046988:Proteasome Endopeptidase Complex; D012697:Serine Endopeptidases; D000097625:HLA-E Antigens; C067713:lactacystin; C026515:type I signal peptidase; C061553:ATP dependent 26S protease; C078846:epoxomicin