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Title: The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53
Author: Hongmei Liu , Xiaoling Li , Guozhu Ning , Shu Zhu , Xiaolu Ma, Xiuli Liu, Chunying Liu, Min Huang, Ina Schmitt, Ullrich Wüllner, Yamei Niu, Caixia Guo , Qiang Wang , Tie-Shan Tang
Abstract: 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.
Corresponding author: Caixia Guo , Qiang Wang , Tie-Shan Tang
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PubYear: 2016
Issue: DOI:10.1371/journal.pbio.2000733
Journal: PLoS Biol
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URL: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000733