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.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Ikeh MA,Kastora SL,Day AM,Herrero-de-Dios CM,Tarrant E,Waldron KJ,Banks AP,Bain JM,Lydall D,Veal EA,MacCallum DM,Erwig LP,Brown AJ,Quinn Jdoi
10.1091/mbc.E16-05-0266subject
Has Abstractpub_date
2016-09-01 00:00:00pages
2784-801issue
17eissn
1059-1524issn
1939-4586pii
mbc.E16-05-0266journal_volume
27pub_type
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