期刊
MBIO
卷 9, 期 2, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/mBio.02229-17
关键词
Candida albicans; MAP kinase signaling; nitrosative stress
类别
资金
- Centre for Genome Enabled Biology and Medicine, Aberdeen Proteomics
- Iain Fraser Cytometry Centre
- Microscopy and Histology Facility
- qPCR facility at the University of Aberdeen
- UK Biotechnology and Biological Research Council [BB/K017365/1, BB/F00513X/1, BB/K016393/1]
- European Research Council (STRIFE advanced grant) [C-2009-AdG-249793]
- UK Medical Research Council [MR/M026663/1, MR/M000923/1]
- Wellcome Trust [097377]
- MRC Centre for Medical Mycology [MR/M026663/1]
- University of Aberdeen [MR/M026663/1]
- Biotechnology and Biological Sciences Research Council [BB/K017365/1, BB/K016393/1, BB/P020119/1, BB/F00513X/1] Funding Source: researchfish
- Medical Research Council [MR/M026663/1, MR/N006364/1] Funding Source: researchfish
- BBSRC [BB/K017365/1, BB/K016393/1, BB/F00513X/1, BB/P020119/1] Funding Source: UKRI
- MRC [MR/M026663/1, MR/N006364/1] Funding Source: UKRI
In all eukaryotic kingdoms, mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses to environmental cues. These MAPKs are activated by phosphorylation at highly conserved threonine and tyrosine residues in response to specific inputs, leading to their accumulation in the nucleus and the activation of their downstream targets. A specific MAP kinase can regulate different downstream targets depending on the nature of the input signal, thereby raising a key question: what defines the stress-specific outputs of MAP kinases? We find that the Hog1 MAPK contributes to nitrosative-stress resistance in Candida albicans even though it displays minimal stress-induced phosphorylation under these conditions. We show that Hog1 becomes oxidized in response to nitrosative stress, accumulates in the nucleus, and regulates the nitrosative stress-induced transcriptome. Mutation of specific cysteine residues revealed that C156 and C161 function together to promote stress resistance, Hog1-mediated nitrosative-stress-induced gene expression, resistance to phagocytic killing, and C. albicans virulence. We propose that the oxidation of Hog1, rather than its phosphorylation, contributes to the nitrosative-stressspecific responses of this MAP kinase. IMPORTANCE Mitogen-activated protein kinases play key roles in the responses of eukaryotic cells to extracellular signals and are critical for environmental-stress resistance. The widely accepted paradigm is that MAP kinases are activated by phosphorylation, which then triggers their nuclear accumulation and the activation of target proteins and genes that promote cellular adaptation. Our data suggest that alternative forms of posttranslational modification can modulate MAP kinase functionality in Candida albicans. We demonstrate that Hog1 is not significantly phosphorylated in response to nitrosative stress, yet it displays nuclear accumulation and contributes to the global transcriptional response to this stress, as well as promoting nitrosative-stress resistance. Instead, nitrosative stress triggers changes in the redox status of Hog1. We also show that specific Hog1 cysteine residues influence its activation of stress genes. Therefore, alternative posttranslational modifications appear to regulate the stress-specific outputs of MAP kinases.
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