Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
Nucleic Acids Res. 2023 Aug 25;51(15):8133-8149. doi: 10.1093/nar/gkad564.
Fungal pathogens threaten ecosystems and human health. Understanding the molecular basis of their virulence is key to develop new treatment strategies. Here, we characterize NCS2*, a point mutation identified in a clinical baker's yeast isolate. Ncs2 is essential for 2-thiolation of tRNA and the NCS2* mutation leads to increased thiolation at body temperature. NCS2* yeast exhibits enhanced fitness when grown at elevated temperatures or when exposed to oxidative stress, inhibition of nutrient signalling, and cell-wall stress. Importantly, Ncs2* alters the interaction and stability of the thiolase complex likely mediated by nucleotide binding. The absence of 2-thiolation abrogates the in vivo virulence of pathogenic baker's yeast in infected mice. Finally, hypomodification triggers changes in colony morphology and hyphae formation in the common commensal pathogen Candida albicans resulting in decreased virulence in a human cell culture model. These findings demonstrate that 2-thiolation of tRNA acts as a key mediator of fungal virulence and reveal new mechanistic insights into the function of the highly conserved tRNA-thiolase complex.
真菌病原体威胁着生态系统和人类健康。了解其毒力的分子基础是开发新治疗策略的关键。在这里，我们描述了 NCS2*，这是在临床面包酵母分离株中发现的点突变。Ncs2 是 tRNA 2-硫代的必需酶，NCS2突变导致在体温下增加硫代。在高温下生长或暴露于氧化应激、营养信号抑制和细胞壁应激时，NCS2酵母表现出增强的适应性。重要的是，Ncs2*改变了硫醇酶复合物的相互作用和稳定性，可能是通过核苷酸结合介导的。2-硫代的缺失消除了感染小鼠体内致病性面包酵母的体内毒力。最后，低修饰触发了常见共生病原体白色念珠菌的菌落形态和菌丝形成的变化，导致在人类细胞培养模型中的毒力降低。这些发现表明，tRNA 的 2-硫代作用是真菌毒力的关键调节剂，并揭示了高度保守的 tRNA-硫醇酶复合物功能的新机制见解。
