Transcriptome profile of S. cerevisiae treated with tauroursodeoxycholic acid (TUDCA)

Cells respond to endoplasmic reticulum (ER) stress through activation of signaling pathways such as the Unfolded Protein Response (UPR) which improve the ER folding environment capacity upon changes in misfolded protein burden. Small molecules termed chemical chaperones can attenuate the UPR under stress conditions and improve folding and trafficking of specific mutant proteins. One such compound is the bile acid tauroursodeoxycholic acid (TUDCA). Despite promising results in multiple models of protein folding diseases, TUDCA’s mechanism of action remains unclear. To better define how TUDCA attenuate ER stress, we leveraged the genetically tractable budding yeast, S. cerevisiae. Consistent with properties described for TUDCA, we found it significantly improves growth of yeast subjected to ER stress caused by the N-glycosylation inhibitor tunicamycin (Tm) independently of activity of the UPR. In addition to other data, transcriptomics of strains treated with TUDCA link its ability to resuce Tm-induced stress with cell wall remodeling.细胞可通过激活未折叠蛋白反应（Unfolded Protein Response, UPR）等信号通路响应内质网（endoplasmic reticulum, ER）应激，在错配蛋白负荷改变时优化内质网的折叠环境容量。被称为化学分子伴侣（chemical chaperones）的小分子化合物，可在应激条件下减弱未折叠蛋白反应，并改善特定突变蛋白的折叠与转运过程。其中一类典型化合物为胆汁酸类的牛磺熊去氧胆酸（tauroursodeoxycholic acid, TUDCA）。尽管在多种蛋白质折叠疾病模型中已获得颇具前景的实验结果，但TUDCA的具体作用机制仍未阐明。为更清晰地界定TUDCA减弱内质网应激的具体途径，我们利用了遗传操作便捷的酿酒酵母（S. cerevisiae）。与此前关于TUDCA的研究特性相符，我们发现其可显著改善经N-糖基化抑制剂衣霉素（tunicamycin, Tm）诱导内质网应激的酵母菌株的生长，且该作用不依赖未折叠蛋白反应的活性。结合其他实验数据，经TUDCA处理的菌株的转录组学（transcriptomics）分析结果将其缓解衣霉素诱导应激的能力与细胞壁重塑（cell wall remodeling）过程建立了关联。