PUBLICATION

The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

Authors
Liu, H., Li, X., Ning, G., Zhu, S., Ma, X., Liu, X., Liu, C., Huang, M., Schmitt, I., Wüllner, U., Niu, Y., Guo, C., Wang, Q., Tang, T.S.
ID
ZDB-PUB-161117-2
Date
2016
Source
PLoS Biology   14: e2000733 (Journal)
Registered Authors
Wang, Qiang
Keywords
Apoptosis, Zebrafish, Immunoprecipitation, Embryos, Neuronal death, Cell staining, Neurons, Immunoblotting
MeSH Terms
  • Animals
  • Apoptosis*
  • Ataxin-3/metabolism*
  • Machado-Joseph Disease/enzymology*
  • Mice
  • Protein Stability
  • Tumor Suppressor Protein p53/metabolism*
PubMed
27851749 Full text @ PLoS Biol.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping