Prion-Associated Toxicity is Rescued by Elimination of Cotranslational Chaperones.
The nascent polypeptide-associated complex (NAC) is a highly conserved but poorly characterized triad of proteins that bind near the ribosome exit tunnel. The NAC is the first cotranslational factor to bind to polypeptides and assist with their proper folding. Surprisingly, we found that deletion of NAC subunits in Saccharomyces cerevisiae rescues toxicity associated with the strong [PSI+] prion. This counterintuitive finding can be explained by changes in chaperone balance and distribution whereby the folding of the prion protein is improved and the prion is rendered nontoxic. In particular, the ribosome-associated Hsp70 Ssb is redistributed away from Sup35 prion aggregates to the nascent chains, leading to an array of aggregation phenotypes that can mimic both overexpression and deletion of Ssb. This toxicity rescue demonstrates that chaperone modification can block key steps of the prion life cycle and has exciting implications for potential treatment of many human protein conformational disorders.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Kathryn M
KM
Keefer
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Heather L
HL
True
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D015966:Gene Expression Regulation, Fungal; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics*; D010454:Peptide Termination Factors / Q000096:biosynthesis / Q000235:genetics*; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D011328:Prions / Q000737:chemistry / Q000235:genetics* / Q000633:toxicity; D066329:Protein Aggregates / Q000235:genetics; D017510:Protein Folding; D012270:Ribosomes / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics*; D017384:Sequence Deletion
D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D010454:Peptide Termination Factors; D010455:Peptides; D011328:Prions; D066329:Protein Aggregates; C095192:SSB1 protein, S cerevisiae; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C096099:nascent-polypeptide-associated complex