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

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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

DOI 10.1046/j.1365-2958.2003.03508.x

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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.

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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)
ORCID: Heitman, Joseph
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2003-04-29
Volume: 48
Issue: 5
Pages: 1377-1387
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1046/j.1365-2958.2003.03508.x
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: green
europepmc.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
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 › Infectious Diseases › 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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The Cryptococcus neoformans MAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function

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