Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations or stress responses

The protein homeostasis (proteostasis) network maintains balanced protein synthesis, folding, transport and degradation within a cell. Because failure to maintain proteostasis is associated with aging and disease, a concerted effort has been placed on studying how the proteostasis network responds to various stresses. Typically, this is accomplished using ectopic overexpression of well-characterized, model misfolded protein substrates; however, how cells tolerate large-scale, diverse burden to the proteostasis network is not understood. Aneuploidy, the state of imbalanced chromosome content, adversely affects the proteostasis network by dysregulating the expression of hundreds of proteins simultaneously. Using aneuploid yeast cells as a model, we address what compensatory adjustments enable cells to tolerate large-scale, diverse challenges to the proteostasis network. Here we show adapted aneuploid Saccharomyces cerevisiae strains that exhibit robust growth and enhanced stress tolerance associated with enhancement of translation, folding, and quality control systems without genetic changes or activation of canonical stress response pathways.

蛋白质稳态（proteostasis）网络维持细胞内蛋白质合成、折叠、转运与降解的动态平衡。鉴于蛋白稳态失衡与衰老及多种疾病密切相关，学界已协同开展研究以解析蛋白稳态网络响应各类应激刺激的具体机制。通常此类研究多通过对特征明确的模型错误折叠蛋白底物（model misfolded protein substrates）进行异位过表达（ectopic overexpression）来实现，但学界尚未明确细胞如何耐受蛋白稳态网络所承受的大规模、多样化负荷。非整倍性（aneuploidy）即染色体含量失衡的状态，会通过同时失调数百种蛋白质的表达对蛋白稳态网络产生负面影响。本研究以非整倍体酵母细胞为模型，探究何种代偿性调控机制可使细胞耐受蛋白稳态网络所面临的大规模多样化挑战。本文研究结果显示，经过适应性演化的非整倍体酿酒酵母（Saccharomyces cerevisiae）菌株可在未发生遗传改变、未激活经典应激反应通路（canonical stress response pathways）的情况下，展现出旺盛的生长能力与增强的应激耐受性，该表型与翻译、折叠及质量控制系统的强化密切相关。