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

Jessica R. Blount, Wei-Ling Tsou, Gorica Ristic, Aaron A. Burr, Michelle Ouyang, Holland Galante, K. Matthew Scaglione and Sokol V. Todi ()
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Jessica R. Blount: Wayne State University School of Medicine
Wei-Ling Tsou: Wayne State University School of Medicine
Gorica Ristic: Wayne State University School of Medicine
Aaron A. Burr: Wayne State University School of Medicine
Michelle Ouyang: Wayne State University School of Medicine
Holland Galante: Medical College of Wisconsin
K. Matthew Scaglione: Medical College of Wisconsin
Sokol V. Todi: Wayne State University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5638

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