Cited by 218Fungal Infections and StudiesFungal and yeast genetics researchAntifungal resistance and susceptibility

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

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Kraus, Peter R., Fox, Deborah S., Cox, Gary M., Heitman, Joseph·2003·Molecular Microbiology

Abstract

Summary: 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°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 β‐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.

Integrity signals

Registry

Crossref · 10.1046/j.1365-2958.2003.03508.x

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  • The C. glabrata Δcnb1 strain phenotype (increased susceptibility to azoles and cell wall-damaging agents, decreased virulence) is consistent with previous findings for other pathogenic fungi.

    “For example, the observed C. glabrata Δcnb1 strain phenotype, which is characterized by an increased susceptibility to azoles and cell wall-damaging agents as well as decreased virulence, is consistent with previous findings for other pathogenic fungi, such as C. albicans (2-4, 27), C. neoformans (11, 18, 21), and A. fumigatus (9, 30).”
  • The C. albicans cnb1 mutant showed filamentous growth in vivo but failed to grow in a mouse model of disseminated candidiasis and was unable to survive in serum, revealing evolutionarily distinct control aspects of calcineurin over virulence of two divergent fungal pathogens via distinct mechanisms.

    “Although the C. albicans cnb1 mutant strain showed filamentous growth in vivo, it failed to grow in a mouse model of disseminated candidiasis and was unable to survive in serum, revealing evolutionarily distinct control aspects of calcineurin over virulence of two divergent fungal pathogens via distinct mechanisms (Blankenship and Heitman, 2005; Blankenship et al., 2003; Kraus et al., 2003).”

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Authors
Kraus, P. R., Fox, D. S., Cox, G. M., & Heitman, J.
Affiliations
  • Duke Medical Center (US)
  • Howard Hughes Medical Institute (US)
Venue
Molecular Microbiology
Publisher
Wiley
Published
2003-04-29
Volume
48
Issue
5
Pages
1377-1387
ISSN
  • 0950-382X (ISSN-L)
  • 1365-2958
OpenAlex
W1586693095
Cited by
217
References
56
Citations by year
2026: 5 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 8 · 2018: 11 · 2017: 11 · 2016: 18 · 2015: 7 · 2014: 13 · 2013: 10 · 2012: 6
FWCI
9.35
Type
journal article
Language
en
Open access
Locations
  • Molecular Microbiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute
  • National Institute of Allergy and Infectious Diseases (R37AI039115, P01-AI44975, R01AI042159, R01 AI39115, R01AI42159, P01AI044975, R01 AI50438, R01AI050438, R01AI039115)
Topics
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Keywords
Cryptococcus neoformans, Mpk1, cell integrity pathway, calcineurin, antifungal resistance, nikkomycin Z, caspofungin, FK506, chitin synthase inhibition, cell wall integrity, osmotic stabilization, virulence, cryptococcosis, drug synergy
MeSH terms
Animals, Antifungal Agents, Cell Wall, Cryptococcosis, Cryptococcus neoformans, Culture Media, Enzyme Inhibitors, Female, Fungal Proteins, Mice, Inbred DBA, Temperature, Virulence, Gene Expression Regulation, Fungal, Calcineurin, Mitogen-Activated Protein Kinases, Saccharomyces cerevisiae Proteins, Mice, Calcineurin Inhibitors

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