title: Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis.
abstract: 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.
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Mélanie A C
authors.initials: MA
authors.lastname: Ikeh
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Stavroula L
authors.initials: SL
authors.lastname: Kastora
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Day
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Herrero-de-Dios
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Tarrant
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Waldron
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: A Peter
authors.initials: AP
authors.lastname: Banks
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bain
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Lydall
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Veal
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Donna M
authors.initials: DM
authors.lastname: MacCallum
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Erwig
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Alistair J P
authors.initials: AJ
authors.lastname: Brown
authors.affiliation: Institute for Cell and Molecular Biosciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom janet.quinn@ncl.ac.uk.
authors.forename: Janet
authors.initials: J
authors.lastname: Quinn
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism; D006706:Homeostasis; D008670:Metals; D018384:Oxidative Stress / Q000502:physiology; D010710:Phosphates; D029701:Saccharomyces cerevisiae Proteins; D017423:Sequence Analysis, RNA; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014774:Virulence / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D008670:Metals; C060292:PHO4 protein, S cerevisiae; D010710:Phosphates; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D003300:Copper; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1