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

Hongmei Liu,Qiang Wang,Chunying Liu,Xiuli Liu,Min Huang,Caixia Guo,Ullrich Wüllner,Xiaolu Ma,Xiaoling Li,Guozhu Ning,Ina Schmitt,Yamei Niu,Shu Zhu,Tie-Shan Tang

doi:10.1371/journal.pbio.2000733

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.

Highlights

Spinocerebellar ataxia type 3 (SCA3), known as Machado–Joseph disease (MJD), is an autosomal-dominantly inherited ataxia and one of at least nine polyglutamine neurodegenerative disorders described so far [1,2,3]
Ataxin-3 (ATX-3) is a ubiquitously expressed protein that mutated in a neurodegenerative disease called spinocerebellar ataxia type 3 (SCA3)
It has been known for a long time that ATX-3 is a deubiquitinating enzyme (DUB)

Summary

Introduction

Spinocerebellar ataxia type 3 (SCA3), known as Machado–Joseph disease (MJD), is an autosomal-dominantly inherited ataxia and one of at least nine polyglutamine (polyQ) neurodegenerative disorders described so far [1,2,3]. SCA3 is caused by an unstable cytosine-adenineguanine (CAG) trinucleotide expansion mutation in the ATXN3 gene leading to an expanded polyQ tract within the ataxin-3 (ATX-3) protein [4]. ATX-3 has a structured N-terminal Josephin domain comprising the catalytic site, two ubiquitin (Ub)-binding sites, and an unstructured C-terminal, which contains two or three Ub-interacting motifs (UIMs) flanking a polyQ tract [8,9]. The expansion of the polyQ tract is thought to trigger a pathogenic cascade, leading to cellular dysfunction and selective neuronal cell death [10]. The precise pathogenic mechanism triggered by polyQ-expanded ATX-3 in SCA3 patients has remained elusive [11,12,13,14,15,16]

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Conclusion