Prion-dependent proteome remodeling in response to environmental stress is modulated by prion variant and genetic background

A number of fungal proteins are capable of adopting multiple alternative, self-perpetuating prion conformations. These prion variants are associated with functional alterations of the prion-forming protein and thus the generation of new, heritable traits that can be detrimental or beneficial. Here we sought to determine the extent to which the previously-reported ZnCl₂-sensitivity trait of yeast harboring the [<i>PSI</i>⁺] prion is modulated by genetic background and prion variant, and whether this trait is accompanied by prion-dependent proteomic changes that could illuminate its physiological basis. We also examined the degree to which prion variant and genetic background influence other prion-dependent phenotypes. We found that ZnCl₂ exposure not only reduces colony growth but also limits chronological lifespan of [<i>PSI</i>⁺] relative to [<i>psi</i>⁻] cells. This reduction in viability was observed for multiple prion variants in both the S288C and W303 genetic backgrounds. Quantitative proteomic analysis revealed that under exposure to ZnCl₂ the expression of stress response proteins was elevated and the expression of proteins involved in energy metabolism was reduced in [<i>PSI</i>⁺] relative to [<i>psi</i>⁻] cells. These results suggest that cellular stress and slowed growth underlie the phenotypes we observed. More broadly, we found that prion variant and genetic background modulate prion-dependent changes in protein abundance and can profoundly impact viability in diverse environments. Thus, access to a constellation of prion variants combined with the accumulation of genetic variation together have the potential to substantially increase phenotypic diversity within a yeast population, and therefore to enhance its adaptation potential in changing environmental conditions.

多种真菌蛋白质可形成多种不同的、可自我延续的朊病毒（prion）构象。这些朊病毒变体与形成朊病毒的蛋白质的功能改变相关，进而催生新的可遗传性状，此类性状可表现为有害或有益。
本研究旨在探究此前报道的、携带[PSI+]朊病毒的酵母的氯化锌（ZnCl₂）敏感性性状在多大程度上受遗传背景与朊病毒变体的调控，并探究该性状是否伴随有依赖于朊病毒的蛋白质组变化，以阐明其生理基础。我们还检测了朊病毒变体与遗传背景对其他依赖于朊病毒的表型的影响程度。
研究结果显示，相较于[psi−]细胞，氯化锌处理不仅会抑制[PSI+]细胞的菌落生长，还会缩短其时序寿命（chronological lifespan）。在S288C与W303两种遗传背景下，多种朊病毒变体均观察到了此类活力下降现象。
定量蛋白质组学分析（quantitative proteomic analysis）显示，在氯化锌处理条件下，相较于[psi−]细胞，[PSI+]细胞的应激反应蛋白表达上调，而参与能量代谢的蛋白质表达下调。上述结果表明，细胞应激与生长减缓是本研究观测到的表型的核心成因。
从更广泛的视角来看，本研究证实朊病毒变体与遗传背景能够调控依赖于朊病毒的蛋白质丰度变化，并可深刻影响不同环境下的细胞活力。综上，拥有一系列朊病毒变体并结合遗传变异的积累，有望大幅提升酵母种群的表型多样性，进而增强其在变化的环境条件下的适应潜力。