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J. Biol. Chem., Vol. 278, Issue 52, 52102-52115, December 26, 2003

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Pleiotropic Effects of Ubp6 Loss on Drug Sensitivities and Yeast Prion Are Due to Depletion of the Free Ubiquitin Pool^*

Tatiana A. Chernova, Kim D. Allen¶, Lisa M. Wesoloski||, John R. Shanks, Yury O. Chernoff, and Keith D. Wilkinson**

From the Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322 and the School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332

Mutation of the mouse Usp14 gene, encoding the homolog of yeast deubiquitinating enzyme Ubp6, causes ataxia. Here we show that deletion of the UBP6 gene in Saccharomyces cerevisiae causes sensitivity to a broad range of toxic compounds and antagonizes phenotypic expression and de novo induction of the yeast prion [PSI⁺], a functionally defective self-perpetuating isoform of the translation termination factor Sup35. Conversely, overexpression of ubiquitin (Ub) increases phenotypic expression and induction of [PSI⁺] in the wild type cells and suppresses all tested ubp6 defects, indicating that they are primarily due to depletion of cellular Ub levels. Several lines of evidence suggest that Ubp6 functions on the proteasome. First, Ub levels in the ubp6 cells can be partly restored by proteasome inhibitors, suggesting that deletion of Ubp6 decreases Ub levels by increasing proteasome-dependent degradation of Ub. Second, fluorescence microscopy analysis shows that Ubp6-GFP fusion protein is localized to the nucleus of yeast cell, as are most proteasomes. Third, the N-terminal Ub-like domain, although it is not required for nuclear localization of Ubp6, targets Ubp6 to the proteasome and cannot be functionally replaced by Ub. The human ortholog of Ubp6, USP14, probably plays a similar role in higher eukaryotes, since it fully compensates for ubp6 defects and binds to the yeast proteasome. These data link the Ub system to prion expression and propagation and have broad implications for other neuronal inclusion body diseases.

Received for publication, September 16, 2003

^* This work was supported by National Institutes of Health Grants RO1GM30308 and RO1GM23120 (to K. D. W.) and RO1GM58763 (to Y. O. C.). 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.

^¶ Present address: Center for Neurobiology and Behavior, Columbia University, New York, NY 10032.

^|| Present address: Dept. of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90025.

^** To whom correspondence should be addressed: Dept. of Biochemistry, 4017 Rollins Research Bldg., 1510 Clifton Rd., Emory University School of Medicine, Atlanta, GA 30322. Tel.: 404-727-5980; Fax: 404-727-3452; E-mail: genekdw{at}emory.edu.

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