title: Protein Folding Activity of the Ribosome is involved in Yeast Prion Propagation.
abstract: 6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI(+)] using both PFAR-enriched mutants and site-directed methylation. We demonstrate that PFAR is involved in propagation and de novo formation of [PSI(+)]. PFAR and the yeast heat-shock protein Hsp104 partially compensate each other for [PSI(+)] propagation. Our data also provide insight into new functions for the ribosome in basal thermotolerance and heat-shocked protein refolding. PFAR is thus an evolutionarily conserved cell component implicated in the prion life cycle, and we propose that it could be a potential therapeutic target for human protein misfolding diseases.
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Soubigou
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Evrard
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Phu Hai
authors.initials: PH
authors.lastname: Nguyen
authors.affiliation: Yeast Genetics Laboratory, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
authors.forename: Naushaba
authors.initials: N
authors.lastname: Hasin
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CEA, CNRS, Université Paris-Sud, CEA/Saclay, SBIGeM, Gif-sur-Yvette, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Chédin
authors.affiliation: Université de Rennes 1, CNRS UMR 6290 IGDR, Translation and Folding Team, Rennes, France.
authors.forename: Reynald
authors.initials: R
authors.lastname: Gillet
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Contesse
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Friocourt
authors.affiliation: Laboratoire de Biologie Moléculaire Eucaryotes, CNRS, Université de Toulouse, Toulouse, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Stahl
authors.affiliation: Yeast Genetics Laboratory, Department of Biology, Maynooth University, Maynooth, County Kildare, Ireland.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Jones
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
mesh_terms: D006143:Guanabenz / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding / Q000187:drug effects; D012335:RNA, Ribosomal / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C549408:6-aminophenanthridine; D006360:Heat-Shock Proteins; C501335:LTV1 protein, S cerevisiae; D010454:Peptide Termination Factors; D010617:Phenanthridines; D011328:Prions; D012335:RNA, Ribosomal; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C099981:YAR1 protein, S cerevisiae; C070972:HsP104 protein, S cerevisiae; D006143:Guanabenz