title: FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis.
abstract: FAT10 is the only ubiquitin-like modifier that can target proteins for degradation by the proteasome in a ubiquitin-independent manner. The degradation of FAT10-linked proteins by the proteasome is strongly accelerated by the ubiquitin-like-ubiquitin-associated protein NEDD8 ultimate buster-1 long (NUB1L). Here we show how FAT10 and NUB1L dock with the 26S proteasome to initiate proteolysis. We identify the 26S proteasome subunit hRpn10/S5a as the receptor for FAT10, whereas NUB1L can bind to both Rpn10 and Rpn1/S2. Unexpectedly, FAT10 and NUB1L both interact with hRpn10 via the VWA domain. FAT10 degradation in yeast shows that human Rpn10 can functionally reconstitute Rpn10-deficient yeast and that the VWA domain of hRpn10 suffices to enable FAT10 degradation. Depletion of hRpn10 causes an accumulation of FAT10-conjugates also in human cells. In conclusion, we identify the VWA domain of hRpn10 as a receptor for ubiquitin-like proteins within the 26S proteasome and elucidate how FAT10 mediates efficient proteolysis by the proteasome.
authors.affiliation: Division of Immunology, Department of Biology, University of Constance, 78457 Konstanz, Germany.
authors.forename: Neha
authors.initials: N
authors.lastname: Rani
authors.forename: Annette
authors.initials: A
authors.lastname: Aichem
authors.forename: Gunter
authors.initials: G
authors.lastname: Schmidtke
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Kreft
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C430242:NUB1 protein, human; C498506:PSMD4 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C122019:RPN10 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C109184:UBD protein, human; D014452:Ubiquitins; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease