NR AUPP
AU Park,K.W.; Hahn,J.S.; Fan,Q.; Thiele,D.J.; Li,L.
TI De novo appearance and "strain" formation of yeast prion [PSI+] are regulated by the heat-shock transcription factor
QU Genetics 2006 May; 173(1): 35-47
PT journal article
AB 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 hsf1 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 nonpreferable 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.
MH Alleles; *Gene Expression Regulation, Fungal; Heat-Shock Proteins/chemistry/*metabolism; Polyglutamic Acid/chemistry; Prions/*biosynthesis/*metabolism; Protein Structure, Quaternary; Protein Structure, Tertiary; Recombinant Fusion Proteins/metabolism; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Saccharomyces cerevisiae/cytology/genetics/*metabolism; Saccharomyces cerevisiae Proteins/metabolism; Sequence Deletion/genetics; Transcription Factors/chemistry/*metabolism
AD Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Institute of Neuroscience, Feinberg School of Medicine, Chicago, Illinois 60611, USA
SP englisch
PO USA