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. Author summary Mammalian pathogens occupy a diverse set of niches within the host organism. These niches vary in iron and oxygen availability. As a commensal and pathogen of humans, its ability to regulate iron uptake and utilization in response to bioavailable iron level is critical for its survival in different host environments encompassing a broad range of iron levels. This study aims to understand how C . albicans senses and responds to iron level to regulate multiple aspects of its biology. The cytosolic monothiol glutaredoxin Grx3 is a critical regulator of C . albicans iron homeostasis and virulence. Taking a proteomic approach, we identified a large list of Grx3 associated proteins of diverse functions, including iron-sulfur trafficking, iron homeostasis, metabolism redox homeostasis, protein translation, DNA maintenance and repair. In support of these protein associations, Grx3 is important for all these processes. Thus, Grx3 is a global regulator of iron homeostasis and other iron dependent cellular processes.
【초록키워드】 mass spectrometry, Gene Expression, oxygen, iron, metabolism, Protein, DNA, survival, pathogen, humans, Tryptophan, Pathogens, mutant, repression, in vivo, utilization, virulence, expression, Critical, homeostasis, fungal, proteomic, function, Target genes, Candida albicans, regulate, repair, Heat shock, the cell, histidine, target gene, cofactor, essential nutrient, Support, Organisms, Regulation, biological processes, growth, human host, organism, functions, component, sulfur, commensal, leucine, iron homeostasis, Grxs, protein translation, regulatory circuit, cellular processes, Affinity purification, Host, glutaredoxin, approach, Cell, oxidative, genotoxic, performed, conserved, required, applied, amplify, determine, interact, maintain, respond, cytosolic, associations, Candida albican, Taking, 【제목키워드】 iron, Regulation, reveal,