Sup35 methionine oxidation is a trigger forde novo[PSI⁺] prion formation

Abstract

The molecular basis by which fungal and mammalian prions arise spontaneously is poorly understood. A number of different environmental stress conditions are known to increase the frequency of yeast [PSI(+)] prion formation in agreement with the idea that conditions which cause protein misfolding may promote the conversion of normally soluble proteins to their amyloid forms. A recent study from our laboratory has shown that the de novo formation of the [PSI(+)] prion is significantly increased in yeast mutants lacking key antioxidants suggesting that endogenous reactive oxygen species are sufficient to promote prion formation. Our findings strongly implicate oxidative damage of Sup35 as an important trigger for the formation of the heritable [PSI(+)] prion in yeast. This review discusses the mechanisms by which the direct oxidation of Sup35 might lead to structural transitions favoring conversion to the transmissible amyloid-like form. This is analogous to various environmental factors which have been proposed to trigger misfolding of the mammalian prion protein (PrP(C)) into the aggregated scrapie form (PrP(Sc)).

Yeast Models for Amyloids and Prions: Environmental Modulation and Drug Discovery

“…This is in an agreement with the fact that conditions favoring protein misfolding may also favor the conversion of a normally soluble protein into an amyloid form [17,73]. For example, formation of the yeast prion [ PSI + ], an aggregated form of the translation termination factor Sup35, is facilitated by prolonged incubation at low temperature [16], heat stress [74], osmotic and oxidative stresses [75,76], the unfolded protein response and ER stress [34,73,77]. Typically, these effects are detected in the strains containing another protein, such as Rnq1, in an amyloid form.…”

The frequency of yeast [PSI+] prion formation is increased during chronological ageing

“…One possibility is oxidative stress, since ROS-induced protein aggregation and mitochondrial dysfunction is a common feature in age-related diseases 3435. In addition, ROS and oxidative stress are known to induce yeast and mammalian prion formation 36 which may account for increased [ PSI + ] formation observed during chronological ageing. Further research will be required to elucidate the exact signaling pathways and the range of quality control mechanisms that may be modulated through the direct and indirect action of the [ PSI + ] prion during yeast ageing.…”

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

“…Sup35 containing oxidized methionine (MetO) was detected in the atg1 mutant, which appears to underlie the increased frequency of [ PSI + ] prion formation in this mutant. Increasing evidence suggests a causal link between protein oxidation and de novo prion formation ( Grant, 2015 ). For example, oxidized methionine residues detected in misfolded PrP Sc have been proposed to facilitate the structural conversion underlying the sporadic formation of PrP Sc ( DeMarco and Daggett, 2005 ; Wolschner et al , 2009 ; Elmallah et al , 2013 ).…”