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 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.
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Shaun H
SH
Speldewinde
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Victoria A
VA
Doronina
Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom chris.grant@manchester.ac.uk.
Chris M
CM
Grant
D001343:Autophagy / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010084:Oxidation-Reduction / Q000187:drug effects; D010454:Peptide Termination Factors / Q000096:biosynthesis* / Q000235:genetics; D011328:Prions / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics; D013095:Spermidine / Q000494:pharmacology
D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013095:Spermidine