Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs

Carmen Herrero de Dios, Alison M Day, Anna T Tillmann, Stavroula L Kastora, David Stead, Paula S. Salgado, Janet Quinn, Alistair J P Brown* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)
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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-stress-specific responses of this MAP kinase.
Original languageEnglish
Article numbere02229-17
Number of pages16
Issue number2
Early online date27 Mar 2018
Publication statusPublished - 27 Mar 2018

Bibliographical note

Data availability. The RNA sequencing dataset is available at EBI ( under accession number E-MTAB-5990. Other data that support the findings of this study are available from the corresponding author upon reasonable request.

We thank Debbie Smith for constructing the strains JC41 and JC310, Arnab Pradhan for help with DHE control experiments, and our colleagues in the Aberdeen Fungal Group and Newcastle Yeast Group for insightful discussions. We are also grateful to Mike Gustin for his advice. We are grateful to the Centre for Genome Enabled Biology and Medicine, Aberdeen Proteomics, the Iain Fraser Cytometry Centre, the Microscopy and Histology Facility, and the qPCR facility at the University of Aberdeen for their help, advice, and support.

This work was funded by the UK Biotechnology and Biological Research Council ( (grants BB/K017365/1 and BB/F00513X/1 to A.J.P.B. and grant BB/K016393/1 to J.Q.). This work was also supported by the European Research Council ( (STRIFE advanced grant C-2009-AdG-249793 to A.J.P.B.), the UK Medical Research Council ( (grant MR/M026663/1 to A.J.P.B. and grant MR/M000923/1 to P.S.S.), the Wellcome Trust ( (grant 097377 to A.J.P.B. and J.Q.), the MRC Centre for Medical Mycology and the University of Aberdeen (grant MR/M026663/1 to A.J.P.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


  • MAP kinase signalling
  • Hog1
  • post-translational modification
  • nitrosative stress
  • transcript profiling
  • Candida albicans


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