title: Diversity of natural self-derived ligands presented by different HLA class I molecules in transporter antigen processing-deficient cells.
abstract: The transporter associated with antigen processing (TAP) translocates the cytosol-derived proteolytic peptides to the endoplasmic reticulum lumen where they complex with nascent human leukocyte antigen (HLA) class I molecules. Non-functional TAP complexes and viral or tumoral blocking of these transporters leads to reduced HLA class I surface expression and a drastic change in the available peptide repertoire. Using mass spectrometry to analyze complex human leukocyte antigen HLA-bound peptide pools isolated from large numbers of TAP-deficient cells, we identified 334 TAP-independent ligands naturally presented by four different HLA-A, -B, and -C class I molecules with very different TAP dependency from the same cell line. The repertoire of TAP-independent peptides examined favored increased peptide lengths and a lack of strict binding motifs for all four HLA class I molecules studied. The TAP-independent peptidome arose from 182 parental proteins, the majority of which yielded one HLA ligand. In contrast, TAP-independent antigen processing of very few cellular proteins generated multiple HLA ligands. Comparison between TAP-independent peptidome and proteome of several subcellular locations suggests that the secretory vesicle-like organelles could be a relevant source of parental proteins for TAP-independent HLA ligands. Finally, a predominant endoproteolytic peptidase specificity for Arg/Lys or Leu/Phe residues in the P(1) position of the scissile bond was found for the TAP-independent ligands. These data draw a new and intricate picture of TAP-independent pathways.
authors.affiliation: Unidad de Procesamiento Antigénico-Inmunología Viral, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lorente
authors.forename: Susana
authors.initials: S
authors.lastname: Infantes
authors.forename: Eilon
authors.initials: E
authors.lastname: Barnea
authors.forename: Ilan
authors.initials: I
authors.lastname: Beer
authors.forename: Alejandro
authors.initials: A
authors.lastname: Barriga
authors.forename: Noel
authors.initials: N
authors.lastname: García-Medel
authors.forename: Fátima
authors.initials: F
authors.lastname: Lasala
authors.forename: Mercedes
authors.initials: M
authors.lastname: Jiménez
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.forename: Daniel
authors.initials: D
authors.lastname: López
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D017951:Antigen Presentation; D045744:Cell Line, Tumor; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D014644:Genetic Variation / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D013058:Mass Spectrometry; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D059748:Proteolysis
chemical_list: D018528:ATP-Binding Cassette Transporters; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D008024:Ligands; D010455:Peptides; C477327:transporter associated with antigen processing (TAP)
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