title: The FAT10- and ubiquitin-dependent degradation machineries exhibit common and distinct requirements for MHC class I antigen presentation.
abstract: Like ubiquitin (Ub), the ubiquitin-like protein FAT10 can serve as a signal for proteasome-dependent protein degradation. Here, we investigated the contribution of FAT10 substrate modification to MHC class I antigen presentation. We show that N-terminal modification of the human cytomegalovirus-derived pp65 antigen to FAT10 facilitates direct presentation and dendritic cell-mediated cross-presentation of the HLA-A2 restricted pp65(495-503) epitope. Interestingly, our data indicate that the pp65 presentation initiated by either FAT10 or Ub partially relied on the 19S proteasome subunit Rpn10 (S5a). However, FAT10 distinguished itself from Ub in that it promoted a pp65 response which was not influenced by immunoproteasomes or PA28. Further divergence occurred at the level of Ub-binding proteins with NUB1 supporting the pp65 presentation arising from FAT10, while it exerted no effect on that initiated by Ub. Collectively, our data establish FAT10 modification as a distinct and alternative signal for facilitated MHC class I antigen presentation.
authors.affiliation: Institut für Biochemie, Charité-Universitätsmedizin Berlin, Campus CVK, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ebstein
authors.forename: Andrea
authors.initials: A
authors.lastname: Lehmann
authors.forename: Peter-Michael
authors.initials: PM
authors.lastname: Kloetzel
mesh_terms: D017951:Antigen Presentation; D003587:Cytomegalovirus / Q000378:metabolism; D057809:HEK293 Cells; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins; D025801:Ubiquitin / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D009124:Muscle Proteins; C498506:PSMD4 protein, human; C085047:PSME1 protein, human; D010750:Phosphoproteins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C109184:UBD protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; C486207:PSME2 protein, human; D046988:Proteasome Endopeptidase Complex