Sef1-Regulated Iron Regulon Responds to Mitochondria-Dependent Iron–Sulfur Cluster Biosynthesis in Candida albicans

Abstract

Iron homeostasis mechanisms allow the prime commensal-pathogen Candida albicans to cope with the profound shift in iron levels in the mammalian host. The regulators, Sef1 and Sfu1 influence activation and repression of genes required for iron uptake and acquisition by inducing the expression of iron regulon genes in iron-deplete conditions and inactivating them in iron-replete condition. Our study for the first time shows that C. albicans coordinates the activation of the iron regulon with the mitochondrial use of iron for Fe–S cluster biosynthesis, a cellular process that is connected to cellular iron metabolism. We took advantage of a mutant defective in mitochondrial biogenesis ( fzo1 Δ/Δ) to assess the aforesaid link as this mutant exhibited sustained expression of the Sef1 iron regulon, signifying an iron-starved state in the mutant. Our analysis demonstrates that mitochondrion is pivotal for regulation of Fe–S cluster synthesis such that the disruption of this cellular process in fzo1 Δ/Δ cells lead to excessive mitochondrial iron accumulation and reduced activity of the Fe–S cluster-containing enzyme aconitase. Sef1 responds to defective Fe–S cluster synthesis by regulated changes in its subcellular localization; it was retained in the nucleus resulting in the induced expression of the iron regulon. We predict that the mitochondrial Fe–S assembly generates a molecule that is critical for ensuring iron-responsive transcriptional activation of the Sef1 regulon. All told, our data marks Fe–S biogenesis as a mechanism that meshes cellular iron procurement with mitochondrial iron metabolism resulting in regulating the Sef1 regulon in C. albicans .

Global proteomic analysis deciphers the mechanism of action of plant derived oleic acid against Candida albicans virulence and biofilm formation

“…In C. albicans, iron is an important micronutrient which controls its pathogenicity where survival of this pathogen in host depends on iron homeostasis by regulating iron uptake and storage 71 . In addition, C. albicans consist of tripartite system of transcription factors such as Sef1 (Zn 2 Cys 6 DNA-binding protein), Sfu1 (GATA factor), and Hap43 (CCAAT binding complex) to control iron homeostasis 72 . These transcriptional regulators (Sef1 and Rim101) activate the virulence genes expression during iron deprivation.…”

Genome Sequence and Analysis of the Flavinogenic Yeast Candida membranifaciens IST 626

“…In C. albicans , the activation of the iron regulon by Sef1 is co-ordinated with the biosynthesis of iron–sulfur clusters in the mitochondria [ 78 ]. Homologs of the genes involved in iron–sulfur cluster assembly were also identified in C. membranifaciens IST 626 genome ( Table 3 ).…”

MSS2 maintains mitochondrial function and is required for chitosan resistance, invasive growth, biofilm formation and virulence in Candida albicans

“…First, two independent mss2Δ strains exhibited significantly impaired cell growth upon chitosan treatment ( Figure 1a and Supplementary Table S3), although the role of MSS2 in C. albicans has not yet been determined. Second, the Ssn3-regulated gene SEF1 is involved in mitochondrial iron metabolism [ 83 ]. Third, both the Ras1-cAMP and Hog1 MAP kinase pathways have been shown to be important for maintaining mitochondrial activity [ 84 , 85 ].…”