Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

Déborah Tribouillard-Tanvier (1) , Suzana dos Reis (2) , Fabienne Gug (3) , Cécile Voisset (4) , Vincent Béringue (5) , Raimon Sabate (2) , Ema Kikovska , Nicolas Talarek , Stéphane Bach (1) , Chenhui Huang , Nathalie Desban (6) , Sven J Saupe , Surachai Supattapone , Jean-Yves Thuret (7) , Stéphane Chédin (8) , Didier Vilette (9) , Hervé Galons (3) , Suparna Sanyal , Marc Blondel (10)

1 P3H - Phophorylation de protéines et Pathologies Humaines
2 IBGC - Institut de biochimie et génétique cellulaires
3 PMC - UMR_S 648 - Pharmacochimie Moléculaire et Cellulaire
4 ARVHC - Assemblage et réplication du virus de l'hépatite C
5 VIM (UR 0892) - Unité de recherche Virologie et Immunologie Moléculaires
6 SBR - Station biologique de Roscoff = Roscoff Marine Station
7 FRE 3377 - Génétique moléculaire et destin cellulaire
8 SBIGeM - Service de Biologie Intégrative et Génétique Moléculaire
9 IHAP - Interactions hôtes-agents pathogènes [Toulouse]
10 Génétique moléculaire et génétique épidémiologique

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.

Domaines: Biochimie [q-bio.BM]; Biologie moléculaire; Biologie cellulaire

Déborah Tribouillard-Tanvier, Suzana dos Reis, Fabienne Gug, Cécile Voisset, Vincent Béringue, et al.. Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs. PLoS ONE, 2008, 3 (5), pp.e2174. ⟨10.1371/journal.pone.0002174⟩. ⟨hal-02134950⟩