Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun 2014 Aug 21;5:4638
Date
08/22/2014Pubmed ID
25144244Pubmed Central ID
PMC4237202DOI
10.1038/ncomms5638Scopus ID
2-s2.0-84907313542 (requires institutional sign-in at Scopus site) 59 CitationsAbstract
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.
Author List
Blount JR, Tsou WL, Ristic G, Burr AA, Ouyang M, Galante H, Scaglione KM, Todi SVMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Genetically Modified
Ataxin-3
Binding Sites
DNA Repair Enzymes
DNA-Binding Proteins
Drosophila melanogaster
Gene Knockdown Techniques
HeLa Cells
Humans
Proteasome Endopeptidase Complex
Repressor Proteins
Ubiquitin
Ubiquitination
