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J. Biol. Chem., Vol. 282, Issue 5, 3004-3013, February 2, 2007

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Effects of Ubiquitin System Alterations on the Formation and Loss of a Yeast Prion^*

Kim D. Allen¹², Tatiana A. Chernova¹, E. Paula Tennant, Keith D. Wilkinson, and Yury O. Chernoff³

From the School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332-0230 and the Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322

The yeast prion [PSI⁺] is a self-propagating amyloidogenic isoform of the translation termination factor Sup35. Overproduction of the chaperone protein Hsp104 results in loss of [PSI⁺]. Here we demonstrate that this effect is decreased by deletion of either the gene coding for one of the major yeast ubiquitin-conjugating enzymes, Ubc4, or the gene coding for the ubiquitin-recycling enzyme, Ubp6. The effect of ubc4 on [PSI⁺] loss was increased by depletion of the Hsp70 chaperone Ssb but was not influenced by depletion of Ubp6. This indicates that Ubc4 affects [PSI⁺] loss via a pathway that is the same as the one affected by Ubp6 but not by Ssb. In the presence of Rnq1 protein, ubc4 also facilitates spontaneous de novo formation of [PSI⁺]. This stimulation is independent of [PIN⁺], the prion isoform of Rnq1. Numerous attempts failed to detect ubiquitinated Sup35 in the yeast extracts. While ubc4 and other alterations of ubiquitin system used in this work cause slight induction of some Hsps, these changes are insufficient to explain their effect on [PSI⁺]. However, ubc4 increases the proportion of the Hsp70 chaperone Ssa bound to Sup35, suggesting that misfolded Sup35 is either more abundant or more accessible to the chaperones in the absence of Ubc4. The proportion of [PSI⁺] cells containing large aggregated Sup35 structures is also increased by ubc4. We propose that UPS alterations induce an adaptive response, resulting in accumulation of the large "aggresome"-like aggregates that promote de novo prion generation and prion recovery from the chaperone treatment.

Received for publication, October 11, 2006 , and in revised form, November 21, 2006.

^* This work was supported by National Institutes of Health Grants GM58763 (to Y. O. C.) and GM30308 (to K. D. W.). 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.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to the paper.

² Recipient of the Graduate Assistance in the Areas of National Needs (GAANN) fellowship from the Department of Education and by a Suddath Award from the Institute for Bioengineering and Bioscience, Georgia Institute of Technology. Present address: Center for Neurobiology and Behavior, Columbia University, New York, NY 10032.

³ To whom correspondence should be addressed: School of Biology, Georgia Institute of Technology M/C 0230, 310 Ferst Dr., Atlanta, GA 30332-0230. Tel.: 404-894-1157; Fax: 404-894-0519; E-mail: yury.chernoff{at}biology.gatech.edu.

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