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Nat Commun. 2014 Aug 21;5:4638. doi: 10.1038/ncomms5638.

Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23.

Author information

1
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].
2
Department of Pharmacology, Wayne State University School of Medicine, 540 E Canfield, Scott Hall Room 3108, Detroit, Michigan 48201, USA.
3
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.
4
Department of Biochemistry and Neuroscience Research Center, Medical College of Wisconsin, BC038, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA.
5
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.

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.

PMID:
25144244
PMCID:
PMC4237202
DOI:
10.1038/ncomms5638
[Indexed for MEDLINE]
Free PMC Article

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