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Proteasome Control of [URE3] Prion Propagation by Degradation of Anti-Prion Proteins Cur1 and Btn2 in Saccharomyces cerevisiae
Authors:Herman K Edskes  Emily E Stroobant  Morgan P DeWilde  Evgeny E Bezsonov  Reed B Wickner
Institution:Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA
Abstract:URE3] is a prion of the nitrogen catabolism controller, Ure2p, and PSI+] is a prion of the translation termination factor Sup35p in S. cerevisiae. Btn2p cures URE3] by sequestration of Ure2p amyloid filaments. Cur1p, paralogous to Btn2p, also cures URE3], but by a different (unknown) mechanism. We find that an array of mutations impairing proteasome assembly or MG132 inhibition of proteasome activity result in loss of URE3]. In proportion to their prion—curing effects, each mutation affecting proteasomes elevates the cellular concentration of the anti-prion proteins Btn2 and Cur1. Of >4,600 proteins detected by SILAC, Btn2p was easily the most overexpressed in a pre9Δ (α3 core subunit) strain. Indeed, deletion of BTN2 and CUR1 prevents the prion—curing effects of proteasome impairment. Surprisingly, the 15 most unstable yeast proteins are not increased in pre9Δ cells suggesting altered proteasome specificity rather than simple inactivation. Hsp42, a chaperone that cooperates with Btn2 and Cur1 in curing URE3], is also necessary for the curing produced by proteasome defects, although Hsp42p levels are not substantially altered by a proteasome defect. We find that pre9Δ and proteasome chaperone mutants that most efficiently lose URE3], do not destabilize PSI+] or alter cellular levels of Sup35p. A tof2 mutation or deletion likewise destabilizes URE3], and elevates Btn2p, suggesting that Tof2p deficiency inactivates proteasomes. We suggest that when proteasomes are saturated with denatured/misfolded proteins, their reduced degradation of Btn2p and Cur1p automatically upregulates these aggregate-handling systems to assist in the clean-up.
Keywords:Tof2  Btn2  Cur1  [URE3]  prion  proteasome  Pre9  SILAC  Irc25  Poc4
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