| 论文题目： | The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53 |
| 论文题目英文： | |
| 作者： | 刘红美①，李晓玲①，宁国柱①，朱姝①，#Xiao-Lu Ma，刘修利，#Chun-Ying Liu，#Min Huang，#Ina Schmitt，#Ullrich Wüllner，#Ya-Mei Niu，#郭彩霞*，王强*，唐铁山* |
| 论文出处： | |
| 年： | 2016 |
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| 期： | DOI:10.1371/journal.pbio.2000733 |
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| 联系作者： | #郭彩霞，王强，唐铁山 |
| 发表期刊： | PLoS Biol |
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| 论文连接 | http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000733 |
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| 摘要: | As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish. Furthermore, the polyglutamine (polyQ)-expanded ATX-3 retains enhanced interaction and deubiquitination catalytic activity to p53 and causes more severe p53-dependent neurodegeneration in zebrafish brains and in the substantia nigra pars compacta (SNpc) or striatum of a transgenic SCA3 mouse model. Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis. |
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