title: Identification of a lysosomal peptide transport system induced during dendritic cell development.
abstract: The delivery of protein fragments to major histocompatibility complex (MHC)-loading compartments of professional antigen-presenting cells is essential in the adaptive immune response against pathogens. Apart from the crucial role of the transporter associated with antigen processing (TAP) for peptide loading of MHC class I molecules in the endoplasmic reticulum, TAP-independent translocation pathways have been proposed but not identified so far. Based on its overlapping substrate specificity with TAP, we herein investigated the ABC transporter ABCB9, also named TAP-like (TAPL). Remarkably, TAPL expression is strongly induced during differentiation of monocytes to dendritic cells and to macrophages. TAPL does not, however, restore MHC class I surface expression in TAP-deficient cells, demonstrating that TAPL alone or in combination with single TAP subunits does not form a functional transport complex required for peptide loading of MHC I in the endoplasmic reticulum. In fact, by using quantitative immunofluorescence and subcellular fractionation, TAPL was detected in the lysosomal compartment co-localizing with the lysosome-associated membrane protein LAMP-2. By in vitro assays, we demonstrate a TAPL-specific translocation of peptides into isolated lysosomes, which strictly requires ATP hydrolysis. These results suggest a mechanism by which antigenic peptides have access to the lysosomal compartment in professional antigen-presenting cells.
authors.affiliation: Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, Frankfurt, Germany.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Demirel
authors.forename: Zoe
authors.initials: Z
authors.lastname: Waibler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Frank
authors.initials: F
authors.lastname: Grünebach
authors.forename: Silke
authors.initials: S
authors.lastname: Appel
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.forename: Andrej
authors.initials: A
authors.lastname: Hasilik
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
authors.forename: Rupert
authors.initials: R
authors.lastname: Abele
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry*; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells; D000941:Antigens / Q000737:chemistry; D001692:Biological Transport; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008247:Lysosomes / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*
chemical_list: C412573:ABCB9 protein, human; D018528:ATP-Binding Cassette Transporters; D000941:Antigens; D018950:Lipopolysaccharide Receptors; D010455:Peptides