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Proteolysis suppresses spontaneous prion generation in yeast
Atsushi Okamoto1, Nao Hosoda1, Anri Tanaka1
1Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
The Journal of Biological Chemistry
|October 18, 2017
Summary
Yeast proteases cleave Sup35, preventing new prion formation. This discovery reveals a cellular defense against prions, using the yeast [PSI+] prion model to study neurodegenerative diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Prions are infectious proteins causing fatal neurodegenerative diseases like Creutzfeldt-Jakob disease.
- The yeast [PSI+] prion, formed by Sup35, is a key model for studying prion diseases.
- Cellular defense mechanisms against prion formation remain largely unknown.
Purpose of the Study:
- To investigate the cellular defense mechanisms against prion generation in yeast.
- To elucidate the role of Sup35 cleavage in prion suppression.
Main Methods:
- Studied the yeast [PSI+] prion model system.
- Investigated the proteolytic cleavage of the Sup35 protein.
- Utilized gene knockouts (pep4Δ, prb1Δ) and protein overproduction to manipulate protease activity.
- Analyzed prion formation rates under different cleavage conditions.
Main Results:
- Vacuolar proteases PrA and PrB cleave Sup35, removing its N-terminal prion domain.
- Inhibition of Sup35 cleavage increased de novo [PSI+] prion formation up to fivefold.
- Enhanced Sup35 cleavage inhibited [PSI+] prion formation, but did not affect existing prions.
Conclusions:
- Proteolytic cleavage of Sup35 acts as a cellular defense mechanism against prion generation in yeast.
- The yeast [PSI+] model is valuable for understanding prion disease defense mechanisms.
- This finding offers insights into potential strategies against prion diseases and other amyloidoses.