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; Sokol V Todi

doi:10.1038/ncomms5638

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

Journal article

Open access

Peer reviewed

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

Nature communications, Vol.5(1), pp.4638-4638

08/21/2014

DOI: 10.1038/ncomms5638

PMCID: PMC4237202

PMID: 25144244

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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.

Animals

Animals, Genetically Modified

Ataxin-3 - genetics

Ataxin-3 - metabolism

Binding Sites

DNA Repair Enzymes - genetics

DNA Repair Enzymes - metabolism

DNA-Binding Proteins - genetics

DNA-Binding Proteins - metabolism

Drosophila melanogaster - metabolism

Gene Knockdown Techniques

HeLa Cells

Humans

Proteasome Endopeptidase Complex - genetics

Proteasome Endopeptidase Complex - metabolism

Repressor Proteins - genetics

Repressor Proteins - metabolism

Ubiquitin - metabolism

Ubiquitination

Details

Title: Subtitle: Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23
Creators: Jessica R Blount - Wayne State University
Wei-Ling Tsou - Wayne State University
Gorica Ristic - Wayne State University
Aaron A Burr - Wayne State University
Michelle Ouyang - Wayne State University
Holland Galante - Medical College of Wisconsin
K Matthew Scaglione - Medical College of Wisconsin
Sokol V Todi - Wayne State University
Resource Type: Journal article
Publication Details: Nature communications, Vol.5(1), pp.4638-4638
DOI: 10.1038/ncomms5638
PMID: 25144244
PMCID: PMC4237202
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R00 NS073936 / NINDS NIH HHS R01NS086778 / NINDS NIH HHS R00 NS064097 / NINDS NIH HHS R00NS064097 / NINDS NIH HHS T32 CA009531 / NCI NIH HHS R01 NS086778 / NINDS NIH HHS R00NS073936 / NINDS NIH HHS
Language: English
Date published: 08/21/2014
Academic Unit: Radiology
Record Identifier: 9984697718802771

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