Pathogenic fungi must appropriately sense the host availability of essential metals such as Fe. In Candida albicans and other yeasts, sensing of Fe involves mitochondrial Fe-S clusters. Yeast mutants for Fe-S cluster assembly sense Fe limitation even when Fe is abundant and hyperaccumulate Fe. We observe this same disrupted Fe sensing with C. albicans mutants of SMF11, a NRAMP transporter of divalent metals. Mutants of smf11 hyperaccumulate both Mn and Fe and the elevated Mn is secondary to Fe overload. As with Fe-S biogenesis mutants, smf11∆/∆ mutants show upregulation of ferric reductases that are normally repressed under high Fe, and Fe import is activated. However, unlike Fe-S biogenesis mutants, smf11∆/∆ mutants show no defects in mitochondrial Fe-S enzymes. Intriguingly, this exact condition of disrupted Fe sensing without inhibiting Fe-S clusters occurs with C. albicans fre1∆/∆ mutants encoding a ferric reductase. Mutants of fre1 and smf11 display similar perturbations in the cell wall, in filamentation and in the ROS burst of morphogenesis, a Fe-dependent process. As with FRE1, SMF11 is important for virulence in a mouse model for disseminated candidiasis. We propose a model in which FRE1 and SMF11 operate outside the mitochondrial Fe-S pathway to donate ferrous Fe for Fe sensing.

中文翻译：

---

金属转运蛋白 SMF11 和铁还原酶 FRE1 在白色念珠菌铁稳态中的融合作用


病原真菌必须适当地感知宿主对 Fe 等必需金属的可用性。在白色念珠菌和其他酵母中，Fe 的感应涉及线粒体 Fe-S 簇。Fe-S 簇组装的酵母突变体即使 Fe 丰富并且 Fe 过度积累，也会感觉到 Fe 限制。我们用 SMF11 的白色念珠菌突变体观察到同样的 Fe 感应中断，SMF11 是二价金属的 NRAMP 转运蛋白。smf11 的突变体在 Mn 和 Fe 上都过度积累，并且升高的 Mn 继发于 Fe 超负荷。与 Fe-S 生物发生突变体一样，smf11∆/∆ 突变体表现出通常在高 Fe 下被抑制的铁还原酶的上调，并且 Fe 输入被激活。然而，与 Fe-S 生物发生突变体不同，smf11∆/∆ 突变体在线粒体 Fe-S 酶中没有缺陷。有趣的是，这种 Fe 感应中断而不抑制 Fe-S 簇的确切情况发生在编码铁还原酶的白色念珠菌 fre1∆/∆ 突变体中。fre1 和 smf11 的突变体在细胞壁、细丝化和形态发生的 ROS 爆发（一种 Fe 依赖性过程）中表现出类似的扰动。与 FRE1 一样，SMF11 对于播散性念珠菌病小鼠模型中的毒力很重要。我们提出了一个模型，其中 FRE1 和 SMF11 在线粒体 Fe-S 通路之外运行，以提供亚铁 Fe 用于 Fe 感应。