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* Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; and
Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University, Freiburg, Germany
MHC class I molecules present peptides derived from the ectodomains of endogenous transmembrane proteins; however, the processing of these Ags is incompletely understood. As model transmembrane Ags we investigated the processing of MHC-I-derived fusion proteins containing the N-terminally extended Kb-restricted OVA epitope SIINFEKL in the extracytoplasmic domain. In TAP-deficient, nonprofessional APCs, the epitope was cleaved out of various sequence contexts and presented to T cells. Ag presentation was inhibited by acidophilic amines and inhibitors of the vacuolar proton pump, indicating processing in endosomes. Endosomal aspartic-type cathepsins, and to some extent also the trans-Golgi network protease furin, were involved in processing. Clathrin-dependent and independent internalization from the cell surface targeted MHC-I fusion proteins to early and late endosomes, where SIINFEKL/Kb complexes were detected by immunofluorescence microscopy. Targeting of MHC-I fusion proteins to processing compartments was independent of sequence motifs in the cytoplasmic tail. Not only TAP-deficient cells, but also TAP-competent APCs used the vacuolar pathway for processing of MHC-I fusion proteins. Thus, endosomal processing of internalized endogenous transmembrane proteins represents a novel alternate pathway for the generation of MHC-I-binding peptides.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Current address: Institut National de la Santé et de la Recherche Médicale U699, Faculté de Médicine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France.
2 Address correspondence and reprint requests to Dr. Frank Momburg, Department of Molecular Immunology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. E-mail address: f.momburg{at}dkfz.de
3 Abbreviations used in this paper: MHC-I, MHC class I; ER, endoplasmic reticulum; CHX, cycloheximide; CPRG, chlorophenol red-
-D-galactoside; D-PBS, Dulbecco’s PBS; EEA-1, early endosomal Ag 1; EGFP, enhanced GFP; ERAP1, ER-associated aminopeptidase 1; LAMP-1, lysosome-associated membrane protein 1; M6PR, mannose 6-phosphate receptor; siRNA, small interfering RNA; TGN, trans-Golgi network; VAMP-8, vesicle-associated membrane protein 8.
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