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The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function.

Publication ,  Journal Article
Kraus, PR; Fox, DS; Cox, GM; Heitman, J
Published in: Mol Microbiol
June 2003

Cell wall integrity is crucial for fungal growth, development and stress survival. In the model yeast Saccharomyces cerevisiae, the cell integrity Mpk1/Slt2 MAP kinase and calcineurin pathways monitor cell wall integrity and promote cell wall remodelling under stress conditions. We have identified the Cryptococcus neoformans homologue of the S. cerevisiae Mpk1/Slt2 MAP kinase and have characterized its role in the maintenance of cell integrity in response to elevated growth temperature and in the presence of cell wall synthesis inhibitors. C. neoformans Mpk1 is required for growth at 37 degrees C in vitro, and this growth defect is suppressed by osmotic stabilization. C. neoformans mutants lacking Mpk1 are attenuated for virulence in the mouse model of cryptococcosis. Phosphorylation of Mpk1 is induced in response to perturbations of cell wall biosynthesis by the antifungal drugs nikkomycin Z (a chitin synthase inhibitor), caspofungin (a beta-1,3-glucan synthase inhibitor), or FK506 (a calcineurin inhibitor), and mutants lacking Mpk1 display enhanced sensitivity to nikkomycin Z and caspofungin. Lastly, we show that calcineurin and Mpk1 play complementing roles in regulating cell integrity in C. neoformans. Our studies demonstrate that pharmacological inhibition of the cell integrity pathway would enhance the activity of antifungal drugs that target the cell wall.

Duke Scholars

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Published In

Mol Microbiol

DOI

ISSN

0950-382X

Publication Date

June 2003

Volume

48

Issue

5

Start / End Page

1377 / 1387

Location

England

Related Subject Headings

  • Virulence
  • Temperature
  • Saccharomyces cerevisiae Proteins
  • Mitogen-Activated Protein Kinases
  • Microbiology
  • Mice, Inbred DBA
  • Mice
  • Gene Expression Regulation, Fungal
  • Fungal Proteins
  • Female
 

Citation

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Kraus, P. R., Fox, D. S., Cox, G. M., & Heitman, J. (2003). The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function. Mol Microbiol, 48(5), 1377–1387. https://doi.org/10.1046/j.1365-2958.2003.03508.x
Kraus, Peter R., Deborah S. Fox, Gary M. Cox, and Joseph Heitman. “The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function.Mol Microbiol 48, no. 5 (June 2003): 1377–87. https://doi.org/10.1046/j.1365-2958.2003.03508.x.
Kraus, Peter R., et al. “The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function.Mol Microbiol, vol. 48, no. 5, June 2003, pp. 1377–87. Pubmed, doi:10.1046/j.1365-2958.2003.03508.x.
Journal cover image

Published In

Mol Microbiol

DOI

ISSN

0950-382X

Publication Date

June 2003

Volume

48

Issue

5

Start / End Page

1377 / 1387

Location

England

Related Subject Headings

  • Virulence
  • Temperature
  • Saccharomyces cerevisiae Proteins
  • Mitogen-Activated Protein Kinases
  • Microbiology
  • Mice, Inbred DBA
  • Mice
  • Gene Expression Regulation, Fungal
  • Fungal Proteins
  • Female