Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Tribouillard-Tanvier, Déborah; Reis, Suzana Dos; Gug, Fabienne; Voisset, Cécile; Béringue, Vincent; Sabate, Raimon; Kikovska, Ema; Talarek, Nicolas; Bach, Stéphane; Huang, Chenhui; Desban, Nathalie; Saupe, Sven J.; Supattapone, Surachai; Thuret, Jean-Yves; Chédin, Stéphane; Vilette, Didier; Galons, Hervé; Sanyal, Suparna; Blondel, Marc

doi:10.1371/journal.pone.0002174

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Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Tribouillard-Tanvier, Déborah INSERM U613, Brest, France - Univ Brest, Faculté de Médecine et des Sciences de la Santé, UMR-S613, Brest, France - Etablissement Français du Sang (EFS) Bretagne, Brest, France - CHU Brest, Hop Morvan, Laboratoire de Génétique Moléculaire, Brest, France - CNRS UPS2682, Station Biologique, Protein Phosphorylation & Disease Laboratory, Roscoff, France
Reis, Suzana Dos Institute of Cell and Molecular Biology, Uppsala University, Sweden
Gug, Fabienne INSERM U648, Laboratoire de Chimie Organique 2, Université Paris Descartes, France
Voisset, Cécile INSERM U613, Brest, France - Univ Brest, Faculté de Médecine et des Sciences de la Santé, UMR-S613, Brest, France - Etablissement Français du Sang (EFS) Bretagne, Brest, France - CHU Brest, Hop Morvan, Laboratoire de Génétique Moléculaire, Brest, France
Béringue, Vincent Institut National de la Recherche Agronomique (INRA), UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France
Sabate, Raimon Laboratoire de Génétique Moléculaire des Champignons, IBGC UMR CNRS 5095, Université de Bordeaux 2, France
Kikovska, Ema Institute of Cell and Molecular Biology, Uppsala University, Sweden
Talarek, Nicolas Department of Medicine/Biochemistry, University of Fribourg, Switzerland
Bach, Stéphane CNRS UPS2682, Station Biologique, Protein Phosphorylation & Disease Laboratory, Roscoff, France
Huang, Chenhui Institute of Cell and Molecular Biology, Uppsala University, Sweden
Desban, Nathalie CNRS UPS2682, Station Biologique, Protein Phosphorylation & Disease Laboratory, Roscoff, France
Saupe, Sven J. Laboratoire de Génétique Moléculaire des Champignons, IBGC UMR CNRS 5095, Université de Bordeaux 2, France
Supattapone, Surachai Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, USA - Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire, USA
Thuret, Jean-Yves CEA, iBiTec-S, Gif- sur-Yvette, France
Chédin, Stéphane CEA, iBiTec-S, Gif- sur-Yvette, France
Vilette, Didier Institut National de la Recherche Agronomique (INRA), UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France
Galons, Hervé INSERM U648, Laboratoire de Chimie Organique 2, Université Paris Descartes, France
Sanyal, Suparna Institute of Cell and Molecular Biology, Uppsala University, Sweden
Blondel, Marc INSERM U613, Brest, France - Univ Brest, Faculté de Médecine et des Sciences de la Santé, UMR-S613, Brest, France - Etablissement Français du Sang (EFS) Bretagne, Brest, France - CHU Brest, Hop Morvan, Laboratoire de Génétique Moléculaire, Brest, France

14.05.2008

Published in:

PLoS ONE. - 2008, vol. 3, no. 5, p. e2174

English Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

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