Mutable yeast prion variants are stabilized by a defective Hsp104 chaperone.

Area of Science:

• Protein misfolding and aggregation
• Yeast genetics and molecular biology
• Prion biology

Background:

• The Hsp104 chaperone is implicated in prion propagation and curing.
• Previous studies suggested Hsp104 acts as an anti-prion system, curing nascent variants.
• The role of Hsp104 in prion variant stability and emergence requires further investigation.

Purpose of the Study:

• To reassess the role of Hsp104 in prion variant dynamics.
• To investigate the impact of mutant Hsp104 on the emergence and stability of [PSI+] prion variants.
• To clarify the mechanism of Hsp104-induced prion curing.

Main Methods:

• Induction of [PSI+] variants in wild-type and Hsp104 mutant yeast strains.
• Characterization of prion variant properties including thermostability and mutability.
• Assessment of prion curing by excess amounts of wild-type and mutant Hsp104.

Main Results:

• Mutant Hsp104 restricted the emergence of new, mutable prion variants.
• Newly identified variants in the mutant background showed lower thermostability and changed to known variants in wild-type cells.
• Excess Hsp104 (mutant or truncated) effectively cured [PSI+] variants, independent of its N-terminal domain.

Conclusions:

• Mutant Hsp104 can restrict prion variant emergence, conserving transmutable variants.
• The findings challenge the necessity of the Hsp104 N-terminal domain for prion curing.
• This study provides new insights into Hsp104's complex role in prion biology and curing mechanisms.