p45, an ATPase subunit of the 19S proteasome, targets the polyglutamine disease protein ataxin-3 to the proteasome |
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Authors: | Wang Hongfeng Jia Nali Fei Erkang Wang Zhiming Liu Chao Zhang Tao Fan Jun Wu Mian Chen Lin Nukina Nobuyuki Zhou Jiangning Wang Guanghui |
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Affiliation: | Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology, School of Life Sciences, University of Science & Technology of China, PR China. |
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Abstract: | Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by an expansion of the polyglutamine tract near the C-terminus of the MJD-1 gene product, ataxin-3. Ataxin-3 is degraded by the proteasome. However, the precise mechanism of ataxin-3 degradation remains to be elucidated. In this study, we show direct links between ataxin-3 and the proteasome. p45, an ATPase subunit of the 19S proteasome, interacts with ataxin-3 in vitro and stimulates the degradation of ataxin-3 in an in vitro reconstituted degradation assay system. The effect of p45 on ataxin-3 degradation is blocked by MG132, a proteasome inhibitor. In N2a or 293 cells, overexpression of p45 strikingly enhances the clearance of both normal and expanded ataxin-3, but not alpha synuclein or SOD1, implying a functional specificity of p45 in this proteolytic process. The N-terminus of ataxin-3, which serves as a recognition site by p45, is necessary for the proteolytic process of ataxin-3. We also show that other three ATPases of the 19S proteasome, MSS1, p48, and p56 have no effect on ataxin-3 degradation. These data provide evidence that p45 plays an important role in regulating ataxin-3 degradation by the proteasome. |
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Keywords: | ataxin-3 Machado–Joseph disease p45 polyglutamine proteasome ubiquitin |
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