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

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. © 2016 liu et al.