title: The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53.
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.
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Ning
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology and Center for Experimental Animal Research, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College (PUMC), Beijing, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: University of Bonn, Department of Neurology and German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.affiliation: University of Bonn, Department of Neurology and German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.affiliation: Department of Pathology and Center for Experimental Animal Research, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College (PUMC), Beijing, China.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Niu
authors.affiliation: CAS Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D000067699:Ataxin-3 / Q000378:metabolism*; D017827:Machado-Joseph Disease / Q000201:enzymology*; D051379:Mice; D055550:Protein Stability; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D000067699:Ataxin-3