Autophagy protects against de novo formation of the [PSI+] prion in yeast

Prions are self-propagating, infectious proteins that underlie several neurodegenerative diseases. The molecular basis underlying their sporadic formation is poorly understood. We show that autophagy protects against de novo formation of [PSI(+)], which is the prion form of the yeast Sup35 translati...

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Bibliographic Details
Published in:Molecular biology of the cell 2015-12, Vol.26 (25), p.4541-4551
Main Authors: Speldewinde, Shaun H, Doronina, Victoria A, Grant, Chris M
Format: Article
Language:English
Subjects:
Autophagy - genetics
Gene Expression Regulation, Fungal - drug effects
Humans
Mutation
Neurodegenerative Diseases - genetics
Oxidation-Reduction - drug effects
Peptide Termination Factors - biosynthesis
Peptide Termination Factors - genetics
Prions - genetics
Prions - metabolism
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae Proteins - biosynthesis
Saccharomyces cerevisiae Proteins - genetics
Spermidine - pharmacology
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Summary:Prions are self-propagating, infectious proteins that underlie several neurodegenerative diseases. The molecular basis underlying their sporadic formation is poorly understood. We show that autophagy protects against de novo formation of [PSI(+)], which is the prion form of the yeast Sup35 translation termination factor. Autophagy is a cellular degradation system, and preventing autophagy by mutating its core components elevates the frequency of spontaneous [PSI(+)] formation. Conversely, increasing autophagic flux by treating cells with the polyamine spermidine suppresses prion formation in mutants that normally show a high frequency of de novo prion formation. Autophagy also protects against the de novo formation of another prion, namely the Rnq1/[PIN(+)] prion, which is not related in sequence to the Sup35/[PSI(+)] prion. We show that growth under anaerobic conditions in the absence of molecular oxygen abrogates Sup35 protein damage and suppresses the high frequency of [PSI(+)] formation in an autophagy mutant. Autophagy therefore normally functions to remove oxidatively damaged Sup35, which accumulates in cells grown under aerobic conditions, but in the absence of autophagy, damaged/misfolded Sup35 undergoes structural transitions favoring its conversion to the propagatable [PSI(+)] form.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e15-08-0548