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During interactions with its mammalian host, the pathogenic yeast Candida albicans is exposed to a range of stresses such as superoxide radicals and cationic fluxes. Unexpectedly, a nonbiased screen of transcription factor deletion mutants revealed that the phosphate-responsive transcription factor Pho4 is vital for the resistance of C. albicans to these diverse stresses. RNA-Seq analysis indicated that Pho4 does not induce stress-protective genes directly. Instead, we show that loss of Pho4 affects metal cation toxicity, accumulation, and bioavailability. We demonstrate that pho4Δ cells are sensitive to metal and nonmetal cations and that Pho4-mediated polyphosphate synthesis mediates manganese resistance. Significantly, we show that Pho4 is important for mediating copper bioavailability to support the activity of the copper/zinc superoxide dismutase Sod1 and that loss of Sod1 activity contributes to the superoxide sensitivity of pho4Δ cells. Consistent with the key role of fungal stress responses in countering host phagocytic defenses, we also report that C. albicans pho4Δ cells are acutely sensitive to macrophage-mediated killing and display attenuated virulence in animal infection models. The novel connections between phosphate metabolism, metal homeostasis, and superoxide stress resistance presented in this study highlight the importance of metabolic adaptation in promoting C. albicans survival in the host.
Pubmed ID: 27385340 RIS Download
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Database of genetic and molecular biological information about Candida albicans. Contains information about genes and proteins, descriptions and classifications of their biological roles, molecular functions, and subcellular localizations, gene, protein, and chromosome sequence information, tools for analysis and comparison of sequences and links to literature information. Each CGD gene or open reading frame has an individual Locus Page. Genetic loci that are not tied to DNA sequence also have Locus Pages. Provides Gene Ontology, GO, to all its users. Three ontologies that comprise GO (Molecular Function, Cellular Component, and Biological Process) are used by multiple databases to annotate gene products, so that this common vocabulary can be used to compare gene products across species. Development of ontologies is ongoing in order to incorporate new information. Data submissions are welcome.
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