Mitogen activated protein kinases SakAHOG1 and MpkC collaborate for Aspergillus fumigatus virulence

Ariane Cristina Mendes de Oliveira Bruder Nascimento, Thaila Fernanda dos Reis, Patrícia Alves de Castro, Juliana I. Hori, Vinícius Leite Pedro Bom, Leandro José de Assis, Leandra Naira Zambelli Ramalho, Marina Campos Rocha, Iran Malavazi, Neil Andrew Brown, Vito Valiante, Axel A. Brakhage, Daisuke Hagiwara, Gustavo H. Goldman

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38 Citations (Scopus)

Abstract

Here, we investigated which stress responses were influenced by the MpkC and SakA mitogen-activated protein kinases of the high-osmolarity glycerol (HOG) pathway in the fungal pathogen Aspergillus fumigatus. The ΔsakA and the double ΔmpkC ΔsakA mutants were more sensitive to osmotic and oxidative stresses, and to cell wall damaging agents. Both MpkC::GFP and SakA::GFP translocated to the nucleus upon osmotic stress and cell wall damage, with SakA::GFP showing a quicker response. The phosphorylation state of MpkA was determined post exposure to high concentrations of congo red and Sorbitol. In the wild-type strain, MpkA phosphorylation levels progressively increased in both treatments. In contrast, the ΔsakA mutant had reduced MpkA phosphorylation, and surprisingly, the double ΔmpkC ΔsakA had no detectable MpkA phosphorylation. A. fumigatus ΔsakA and ΔmpkC were virulent in mouse survival experiments, but they had a 40% reduction in fungal burden. In contrast, the ΔmpkC ΔsakA double mutant showed highly attenuated virulence, with approximately 50% mice surviving and a 75% reduction in fungal burden. We propose that both cell wall integrity (CWI) and HOG pathways collaborate, and that MpkC could act by modulating SakA activity upon exposure to several types of stresses and during CW biosynthesis. We investigated which stress responses were influenced by the MpkC and SakA mitogen-activated protein (MAP) kinases of the high-osmolarity glycerol (HOG) pathway in the fungal pathogen Aspergillus fumigatus. The ΔsakA and the double ΔmpkC ΔsakA mutants were more sensitive to osmotic and oxidative stresses, and to cell wall damaging agents. A. fumigatus ΔsakA and ΔmpkC were virulent in mouse survival experiments. In contrast, the ΔmpkC ΔsakA double mutant showed highly attenuated virulence. We propose that both Cell Wall Integrity (CWI) and HOG pathways collaborate, and that MpkC could act by modulating SakA activity upon exposure to several types of stresses and during cell wall biosynthesis.

Original languageEnglish
Pages (from-to)841-859
Number of pages19
JournalMolecular Microbiology
Volume100
Issue number5
Early online date15 Feb 2016
DOIs
Publication statusPublished - 1 Jun 2016

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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    Bruder Nascimento, A. C. M. D. O., dos Reis, T. F., de Castro, P. A., Hori, J. I., Bom, V. L. P., de Assis, L. J., Ramalho, L. N. Z., Rocha, M. C., Malavazi, I., Brown, N. A., Valiante, V., Brakhage, A. A., Hagiwara, D., & Goldman, G. H. (2016). Mitogen activated protein kinases SakAHOG1 and MpkC collaborate for Aspergillus fumigatus virulence. Molecular Microbiology, 100(5), 841-859. https://doi.org/10.1111/mmi.13354