Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 27, Issue 17, Pages 2784-2801Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E16-05-0266
Keywords
-
Categories
Funding
- Medical Research Council
- Wellcome Trust [089930, 080088, 097377]
- Biotechnology and Biological Sciences Research Council [BB/K016393/1, BB/F00513X/1, BB/K017365/1]
- European Research Council STRIFE Advanced Grant [ERC-2009-AdG-249793]
- Royal Society [098375/Z/12/Z]
- Biotechnology and Biological Sciences Research Council [BB/M012360/1, BB/K017365/1, BB/K016393/1, BB/M002314/1, BB/F00513X/1] Funding Source: researchfish
- Cancer Research UK [13314] Funding Source: researchfish
- Medical Research Council [MR/N006364/1, MR/L001284/1] Funding Source: researchfish
- BBSRC [BB/K017365/1, BB/M012360/1, BB/M002314/1, BB/F00513X/1, BB/K016393/1] Funding Source: UKRI
- MRC [MR/N006364/1, MR/L001284/1] Funding Source: UKRI
Ask authors/readers for more resources
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 pho4. 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 pho4. cells. Consistent with the key role of fungal stress responses in countering host phagocytic defenses, we also report that C. albicans pho4. 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available