ABSTRACT
It is no longer necessary to demonstrate that ribosome is the central machinery of protein synthesis. But it is less known that it is also key player of the protein folding process through another conserved function: the protein folding activity of the ribosome (PFAR). This ribozyme activity, discovered more than 2 decades ago, depends upon the domain V of the large rRNA within the large subunit of the ribosome. Surprisingly, we discovered that anti-prion compounds are also potent PFAR inhibitors, highlighting an unexpected link between PFAR and prion propagation.
In this review, we discuss the ancestral origin of PFAR in the light of the ancient RNA world hypothesis. We also consider how this ribosomal activity fits into the landscape of cellular protein chaperones involved in the appearance and propagation of prions and other amyloids in mammals. Finally, we examine how drugs targeting the protein folding activity of the ribosome could be active against mammalian prion and other protein aggregation-based diseases, making PFAR a promising therapeutic target for various human protein misfolding diseases.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors declare no competing financial interests in relation to the work described.
ACKNOWLEDGMENT
We thank E. Giudice for generously helping preparing .
FUNDING
This work was supported by FA29 and défi organization to CV and MB, Agence Nationale pour la Recherche and Direction Générale de l'Armement (ANR-14-ASTR-0001) and Institut Universitaire de France to RG.