Iron is an essential nutrient required as a cofactor for many biological processes. As a fungal commensal-pathogen of humans, Candida albicans encounters a range of bioavailable iron levels in the human host and maintains homeostasis with a conserved regulatory circuit. How C. albicans senses and responds to iron availability is unknown. In model yeasts, regulation of the iron homeostasis circuit requires monothiol glutaredoxins (Grxs), but their functions beyond the regulatory circuit are unclear. Here, we show Grx3 is required for virulence and growth on low iron for C. albicans. To explore the global roles of Grx3, we applied a proteomic approach and performed in vivo cross-linked tandem affinity purification coupled with mass spectrometry. We identified a large number of Grx3 interacting proteins that function in diverse biological processes. This included Fra1 and Bol2/Fra2, which function with Grxs in intracellular iron trafficking in other organisms. Grx3 interacts with and regulates the activity of Sfu1 and Hap43, components of the C. albicans iron regulatory circuit. Unlike the regulatory circuit, which determines expression or repression of target genes in response to iron availability, Grx3 amplifies levels of gene expression or repression. Consistent with the proteomic data, the grx3 mutant is sensitive to heat shock, oxidative, nitrosative, and genotoxic stresses, and shows growth dependence on histidine, leucine, and tryptophan. We suggest Grx3 is a conserved global regulator of iron-dependent processes occurring within the cell.

铁是许多生物过程的辅助因子所必需的必需营养素。作为人类的真菌共生病原体，白色念珠菌在人类宿主中遇到一系列生物可利用的铁水平，并通过保守的调节回路维持体内平衡。如何C . 白化病患者对铁可用性的感知和反应尚不清楚。在模型酵母中，铁稳态回路的调节需要单硫醇谷氧还蛋白 (Grxs)，但它们在调节回路之外的功能尚不清楚。在这里，我们表明 Grx3 是C低铁的毒力和生长所必需的。白化病患者。为了探索 Grx3 的全局作用，我们应用了蛋白质组学方法并在体内进行交联串联亲和纯化与质谱联用。我们确定了大量在不同生物过程中起作用的 Grx3 相互作用蛋白。这包括 Fra1 和 Bol2/Fra2，它们与 Grxs 在其他生物体的细胞内铁运输中发挥作用。Grx3 与C的组分 Sfu1 和 Hap43 相互作用并调节其活性。白色念珠菌铁调节电路。与根据铁的可用性决定靶基因的表达或抑制的调节回路不同，Grx3 放大了基因表达或抑制的水平。与蛋白质组学数据一致，grx3突变体对热休克、氧化、亚硝化和基因毒性胁迫敏感，并表现出对组氨酸、亮氨酸和色氨酸的生长依赖性。我们建议 Grx3 是细胞内发生的铁依赖性过程的保守全局调节器。