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

被引:58
作者
Blount, Jessica R. [1 ,2 ]
Tsou, Wei-Ling [1 ,2 ]
Ristic, Gorica [1 ]
Burr, Aaron A. [1 ,3 ]
Ouyang, Michelle [1 ]
Galante, Holland [4 ]
Scaglione, K. Matthew [4 ]
Todi, Sokol V. [1 ,2 ,3 ]
机构
[1] Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA
[2] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA
[3] Wayne State Univ, Sch Med, Canc Biol Program, Detroit, MI 48201 USA
[4] Med Coll Wisconsin, Dept Biochem & Neurosci Res Ctr, Milwaukee, WI 53226 USA
来源
NATURE COMMUNICATIONS | 2014年 / 5卷
关键词
POLYGLUTAMINE DISEASE PROTEIN; DEUBIQUITINATING ENZYME; RAT MODEL; STRUCTURAL DETERMINANTS; JOSEPHIN DOMAIN; NEURODEGENERATION; DROSOPHILA; TURNOVER; UBE2W;
D O I
10.1038/ncomms5638
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:10
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