Protein Folding Activity of the Ribosome is involved in Yeast Prion Propagation

Area of Science:

• Molecular Biology
• Prion Biology
• Ribosome Function

Background:

• Yeast prions like [PSI(+)] are protein aggregates linked to neurodegenerative diseases.
• 6AP and GA inhibit prions and PFAR, a protein-folding activity in ribosomal RNA.
• The role of PFAR in prion propagation is not well understood.

Purpose of the Study:

• To investigate the involvement of PFAR in the yeast prion [PSI(+)] life cycle.
• To explore the interplay between PFAR and Hsp104 in prion propagation.
• To identify potential therapeutic targets for protein misfolding diseases.

Main Methods:

• Utilized PFAR-enriched mutants and site-directed methylation in yeast models.
• Assessed the impact of PFAR modulation on [PSI(+)] propagation and de novo formation.
• Investigated the functional relationship between PFAR and Hsp104.

Main Results:

• PFAR is essential for both the propagation and de novo formation of the yeast prion [PSI(+)].
• PFAR and the heat-shock protein Hsp104 exhibit partial functional compensation for [PSI(+)] propagation.
• The ribosome, via PFAR, contributes to basal thermotolerance and refolding of heat-shocked proteins.

Conclusions:

• PFAR is an evolutionarily conserved component integral to the prion life cycle.
• PFAR's role extends to ribosome-mediated cellular stress responses.
• PFAR represents a potential therapeutic target for human protein misfolding disorders.