Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G2W1, Canada.
Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
Genetics. 2021 Oct 2;219(2). doi: 10.1093/genetics/iyab131.
Candida albicans is the most common cause of death from fungal infections. The emergence of resistant strains reducing the efficacy of first-line therapy with echinocandins, such as caspofungin calls for the identification of alternative therapeutic strategies. Tra1 is an essential component of the SAGA and NuA4 transcriptional co-activator complexes. As a PIKK family member, Tra1 is characterized by a C-terminal phosphoinositide 3-kinase domain. In Saccharomyces cerevisiae, the assembly and function of SAGA and NuA4 are compromised by a Tra1 variant (Tra1Q3) with three arginine residues in the putative ATP-binding cleft changed to glutamine. Whole transcriptome analysis of the S. cerevisiae tra1Q3 strain highlights Tra1's role in global transcription, stress response, and cell wall integrity. As a result, tra1Q3 increases susceptibility to multiple stressors, including caspofungin. Moreover, the same tra1Q3 allele in the pathogenic yeast C. albicans causes similar phenotypes, suggesting that Tra1 broadly mediates the antifungal response across yeast species. Transcriptional profiling in C. albicans identified 68 genes that were differentially expressed when the tra1Q3 strain was treated with caspofungin, as compared to gene expression changes induced by either tra1Q3 or caspofungin alone. Included in this set were genes involved in cell wall maintenance, adhesion, and filamentous growth. Indeed, the tra1Q3 allele reduces filamentation and other pathogenesis traits in C. albicans. Thus, Tra1 emerges as a promising therapeutic target for fungal infections.
白色念珠菌是真菌感染导致死亡的最常见原因。具有抗药性的菌株的出现降低了棘白菌素类药物（如卡泊芬净）作为一线治疗药物的疗效，因此需要寻找替代的治疗策略。Tra1 是 SAGA 和 NuA4 转录共激活复合物的必需组成部分。作为 PIKK 家族的一员，Tra1 的特征是在 C 末端具有磷酸肌醇 3-激酶结构域。在酿酒酵母中，SAGA 和 NuA4 的组装和功能会因一种具有三个精氨酸残基的 Tra1 变体（Tra1Q3）而受损，该变体的假定 ATP 结合裂隙中的三个精氨酸残基被替换为谷氨酰胺。酿酒酵母 tra1Q3 菌株的全转录组分析强调了 Tra1 在全局转录、应激反应和细胞壁完整性中的作用。因此，tra1Q3 增加了对多种胁迫因素的敏感性，包括卡泊芬净。此外，致病性酵母白色念珠菌中的相同 tra1Q3 等位基因也会引起类似的表型，这表明 Tra1 广泛介导了不同酵母物种的抗真菌反应。在白色念珠菌中的转录谱分析确定了 68 个基因，当 tra1Q3 菌株用卡泊芬净处理时，与单独用 tra1Q3 或卡泊芬净诱导的基因表达变化相比，这些基因的表达存在差异。其中包括与细胞壁维持、黏附和丝状生长相关的基因。事实上，tra1Q3 等位基因降低了白色念珠菌中的丝状形成和其他发病特征。因此，Tra1 成为治疗真菌感染的有希望的靶点。
