The role of Sse1 in the de novo formation and variant determination of the [PSI+] prion.
Yeast prions are a group of non-Mendelian genetic elements transmitted as altered and self-propagating conformations. Extensive studies in the last decade have provided valuable information on the mechanisms responsible for yeast prion propagation. How yeast prions are formed de novo and what cellular factors are required for determining prion "strains" or variants--a single polypeptide capable of existing in multiple conformations to result in distinct heritable phenotypes--continue to defy our understanding. We report here that Sse1, the yeast ortholog of the mammalian heat-shock protein 110 (Hsp110) and a nucleotide exchange factor for Hsp70 proteins, plays an important role in regulating [PSI+] de novo formation and variant determination. Overproduction of the Sse1 chaperone dramatically enhanced [PSI+] formation whereas deletion of SSE1 severely inhibited it. Only an unstable weak [PSI+] variant was formed in SSE1 disrupted cells whereas [PSI+] variants ranging from very strong to very weak were formed in isogenic wild-type cells under identical conditions. Thus, Sse1 is essential for the generation of multiple [PSI+] variants. Mutational analysis further demonstrated that the physical association of Sse1 with Hsp70 but not the ATP hydrolysis activity of Sse1 is required for the formation of multiple [PSI+] variants. Our findings establish a novel role for Sse1 in [PSI+] de novo formation and variant determination, implying that the mammalian Hsp110 may likewise be involved in the etiology of protein-folding diseases.
Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Qing
Q
Fan
Kyung-Won
KW
Park
Zhiqiang
Z
Du
Kevin A
KA
Morano
Liming
L
Li
D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004271:DNA, Fungal / Q000235:genetics; D005800:Genes, Fungal; D014644:Genetic Variation; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins; D009154:Mutation; D010454:Peptide Termination Factors; D010957:Plasmids / Q000235:genetics; D011328:Prions / Q000096:biosynthesis* / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D004271:DNA, Fungal; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D010454:Peptide Termination Factors; D011328:Prions; C494656:SSE1 protein, S cerevisiae; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins