Identification of a lysosomal peptide transport system induced during dendritic cell development.
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.
Demirel
Ozlem
O
Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, Frankfurt, Germany.
Waibler
Zoe
Z
Kalinke
Ulrich
U
Grünebach
Frank
F
Appel
Silke
S
Brossart
Peter
P
Hasilik
Andrej
A
Tampé
Robert
R
Abele
Rupert
R
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*
C412573:ABCB9 protein, human; D018528:ATP-Binding Cassette Transporters; D000941:Antigens; D018950:Lipopolysaccharide Receptors; D010455:Peptides