The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53
- 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.
- PLoS Biology 14: e2000733 (Journal)
- Registered Authors
- Wang, Qiang
- Apoptosis, Zebrafish, Immunoprecipitation, Embryos, Neuronal death, Cell staining, Neurons, Immunoblotting
- MeSH Terms
- Machado-Joseph Disease/enzymology*
- Protein Stability
- Tumor Suppressor Protein p53/metabolism*
- 27851749 Full text @ PLoS Biol.
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. (2016) The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53. PLoS Biology. 14:e2000733.
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
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes