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doi:10.1534/genetics.105.054221
A more recent version of this article appeared on May 1, 2006.
REGULAR RESEARCH PAPERS |
De Novo Appearance and "Strain" Formation of Yeast Prion [PSI+] Are Regulated By the Heat Shock Transcription Factor
Kyung-Won Park 1, Ji-Sook Hahn 2, Qing Fan 1, Dennis Thiele 3 and Liming Li 1*
1 Northwestern University
2 Seoul National University
3 Duke University
* To whom correspondence should be addressed. E-mail: limingli{at}northwestern.edu.
Submitted on December 2, 2005
Revised on January 6, 2006
Accepted on 12 January 2006
ABSTRACT Yeast prions are non-Mendelian genetic elements that are conferred by altered and self-propagating protein conformations. Such a protein conformation-based transmission is similar to that of PrPSc, the infectious protein responsible for prion diseases. Despite recent progress in understanding the molecular nature and epigenetic transmission of prions, the underlying mechanisms governing prion conformational switch and determining prion "strains" are not understood. We report here that the evolutionarily conserved heat shock transcription factor (HSF) strongly influences yeast prion formation and "strain" determination. An HSF mutant lacking the amino-terminal activation domain inhibits the yeast prion [PSI+] formation whereas a mutant lacking the carboxyl-terminal activation domain promotes [PSI+] formation. Moreover, specific [PSI+] "strains" are preferentially formed in these mutants, demonstrating the importance of genetic makeup in determining de novo appearance of prion "strains". Although these hsf1 mutants preferentially support the formation of certain [PSI+] "strains", they are capable of receiving and faithfully propagating non-preferable "strains", suggesting that prion initiation and propagation are distinct processes requiring different cellular components. Our findings establish the importance of HSF in prion initiation and "strain" determination and imply a similar regulatory role of mammalian HSFs in the complex etiology of prion disease.
Key Words: epigenetics, heat shock transcription factor, protein aggregation, protein misfoding disease, yeast prion
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