Cellular turnover of the polyglutamine disease protein ataxin-3 is regulated by its catalytic activity
| Autor: | Sue M. Travis, Sokol V. Todi, Hsiang M. Wen, Mário N. Laço, Henry L. Paulson, Brett J. Winborn |
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| Rok vydání: | 2007 |
| Předmět: |
Proteasome Endopeptidase Complex
Context (language use) Nerve Tissue Proteins Biochemistry Models Biological Catalysis Deubiquitinating enzyme Cell Line Pathogenesis Ubiquitin Chlorocebus aethiops medicine Animals Humans Ataxin-3 Molecular Biology Glutathione Transferase chemistry.chemical_classification biology Nuclear Proteins Cell Biology medicine.disease Repressor Proteins Enzyme chemistry Proteasome Ataxin COS Cells Spinocerebellar ataxia biology.protein Peptides |
| Zdroj: | The Journal of biological chemistry. 282(40) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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