title: Cellular turnover of the polyglutamine disease protein ataxin-3 is regulated by its catalytic activity.
abstract: Ataxin-3, a deubiquitinating enzyme, is the disease protein in spinocerebellar ataxia type 3, one of many neurodegenerative disorders caused by polyglutamine expansion. Little is known about the cellular regulation of ataxin-3. This is an important issue, since growing evidence links disease protein context to pathogenesis in polyglutamine disorders. Expanded ataxin-3, for example, is more neurotoxic in fruit fly models when its active site cysteine is mutated (1). We therefore sought to determine the influence of ataxin-3 enzymatic activity on various cellular properties. Here we present evidence that the catalytic activity of ataxin-3 regulates its cellular turnover, ubiquitination, and subcellular distribution. Cellular protein levels of catalytically inactive ataxin-3 were much higher than those of active ataxin-3, in part reflecting slower degradation. In vitro studies revealed that inactive ataxin-3 was more slowly degraded by the proteasome and that this degradation occurred independent of ubiquitination. Slower degradation of inactive ataxin-3 correlated with reduced interaction with the proteasome shuttle protein, VCP/p97. Enzymatically active ataxin-3 also showed a greater tendency to concentrate in the nucleus, where it colocalized with the proteasome in subnuclear foci. Taken together, these and other findings suggest that the catalytic activity of this disease-linked deubiquitinating enzyme regulates several of its cellular properties, which in turn may influence disease pathogenesis.
authors: Department of Neurology, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Sokol V
authors: SV
authors: Todi
authors: Mario N
authors: MN
authors: Laco
authors: Brett J
authors: BJ
authors: Winborn
authors: Sue M
authors: SM
authors: Travis
authors: Hsiang M
authors: HM
authors: Wen
authors: Henry L
authors: HL
authors: Paulson
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D019556:COS Cells; D002384:Catalysis; D002460:Cell Line; D002522:Chlorocebus aethiops; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D025801:Ubiquitin; C097188:polyglutamine; D005982:Glutathione Transferase; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D046988:Proteasome Endopeptidase Complex