title: Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23.
abstract: Polyglutamine repeat expansion in ataxin-3 causes neurodegeneration in the most common dominant ataxia, spinocerebellar ataxia type 3 (SCA3). Since reducing levels of disease proteins improves pathology in animals, we investigated how ataxin-3 is degraded. Here we show that, unlike most proteins, ataxin-3 turnover does not require its ubiquitination, but is regulated by ubiquitin-binding site 2 (UbS2) on its N terminus. Mutating UbS2 decreases ataxin-3 protein levels in cultured mammalian cells and in Drosophila melanogaster by increasing its proteasomal turnover. Ataxin-3 interacts with the proteasome-associated proteins Rad23A/B through UbS2. Knockdown of Rad23 in cultured cells and in Drosophila results in lower levels of ataxin-3 protein. Importantly, reducing Rad23 suppresses ataxin-3-dependent degeneration in flies. We present a mechanism for ubiquitination-independent degradation that is impeded by protein interactions with proteasome-associated factors. We conclude that UbS2 is a potential target through which to enhance ataxin-3 degradation for SCA3 therapy.
authors.affiliation: 1] Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [2] Department of Neurology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [3].
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Blount
authors.affiliation: 1] Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [2] Department of Neurology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [3].
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Tsou
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA.
authors.forename: Gorica
authors.initials: G
authors.lastname: Ristic
authors.affiliation: 1] Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [2] Cancer Biology Program, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Burr
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Department of Biochemistry and Neuroscience Research Center, Medical College of Wisconsin, BC038, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
authors.forename: Holland
authors.initials: H
authors.lastname: Galante
authors.affiliation: Department of Biochemistry and Neuroscience Research Center, Medical College of Wisconsin, BC038, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
authors.forename: K Matthew
authors.initials: KM
authors.lastname: Scaglione
authors.affiliation: 1] Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [2] Department of Neurology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA [3] Cancer Biology Program, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA.
authors.forename: Sokol V
authors.initials: SV
authors.lastname: Todi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C086985:RAD23A protein, human; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D046988:Proteasome Endopeptidase Complex; D045643:DNA Repair Enzymes