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J. Biol. Chem., Vol. 282, Issue 40, 29348-29358, October 5, 2007

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Cellular Turnover of the Polyglutamine Disease Protein Ataxin-3 Is Regulated by Its Catalytic Activity^*

Sokol V. Todi, Mario N. Laco, Brett J. Winborn^¶, Sue M. Travis, Hsiang M. Wen, and Henry L. Paulson^¶1

From the Department of Neurology and ^¶Graduate Program in Molecular Biology, University of Iowa, Iowa City, Iowa 52242 and the Institute of Biochemistry and Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal

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.

Received for publication, May 18, 2007 , and in revised form, August 1, 2007.

^* This work was supported by a Postdoctoral Research fellowship from the National Ataxia Foundation (to S. V. T.), Portuguese Foundation for Science and Technology Predoctoral fellowship SFRH/BD/17275/2004 (to M. N. L.), a Research Fellowship from the National Ataxia Foundation (to S. M. T.), and National Institutes of Health RO1 Grant NS38712 (to H. L. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed: Dept. of Neurology, EMRB Rm. 240B, University of Iowa, Iowa City, IA 52242. Tel.: 319-335-9859; E-mail: henry-paulson{at}uiowa.edu.

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