Cited by 194Fungal and yeast genetics researchAntifungal resistance and susceptibilityBacterial Genetics and Biotechnology

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The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling.

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Reinoso-Martín, Cristina, Schüller, Christoph, Schuetzer-Muehlbauer, Manuela, Kuchler, Karl·2003·Eukaryotic Cell

DOI 10.1128/ec.2.6.1200-1210.2003PMC PMC326656

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Abstract

The echinocandin caspofungin is a new antifungal drug that blocks cell wall synthesis through inhibition of beta-(1-3)-glucan synthesis. Saccharomyces cerevisiae cells are able to tolerate rather high caspofungin concentrations, displaying high viability at low caspofungin doses. To identify yeast genes implicated in caspofungin tolerance, we performed a genome-wide microarray analysis. Strikingly, caspofungin treatment rapidly induces a set of genes from the protein kinase C (PKC) cell integrity signaling pathway, as well as those required for cell wall maintenance and architecture. The mitogen-activated protein kinase Slt2p is rapidly activated by phosphorylation, triggering signaling through the PKC pathway. Cells lacking genes such as SLT2, BCK1, and PKC1, as well as the caspofungin target gene, FKS1, display pronounced hypersensitivity, demonstrating that the PKC pathway is required for caspofungin tolerance. Notably, the cell surface integrity sensor Wsc1p, but not the sensors Wsc2-4p and Mid2p, is required for sensing caspofungin perturbations. The expression modulation of PKC target genes requires the transcription factor Rlm1p, which controls expression of several cell wall synthesis and maintenance genes. Thus, caspofungin-induced cell wall damage requires Wsc1p as a dedicated sensor to launch a protective response through the activated salvage pathway for de novo cell wall synthesis. Our results establish caspofungin as a specific activator of Slt2p stress signaling in baker's yeast.

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Authors: Reinoso-Martín, C., Schüller, C., Schuetzer-Muehlbauer, M., & Kuchler, K.
Affiliations: Department of Medical Biochemistry, Division of Molecular Genetics, Max F. Perutz Laboratories, University and Biocenter of Vienna, A-1030 Vienna, Austria
Max Perutz Labs (AT)
Corresponding author: Kuchler, Karl
ORCID: Kuchler, Karl
Venue: Eukaryotic Cell
Publisher: American Society for Microbiology
Published: 2003-12
Volume: 2
Issue: 6
Pages: 1200-1210
ISSN: 1535-9778 (ISSN-L)
1535-9786
DOI: 10.1128/ec.2.6.1200-1210.2003
PMC: PMC326656
OpenAlex: W2106031809
Cited by: 193
References: 65
Citations by year: 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 10 · 2021: 11 · 2020: 7 · 2019: 5 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 8 · 2014: 13 · 2013: 7 · 2012: 7
FWCI: 3.68
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Eukaryotic Cell (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: European Commission
Oesterreichische Nationalbank
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords: caspofungin, echinocandins, antifungal drug tolerance, Saccharomyces cerevisiae, protein kinase C signaling, cell integrity pathway, mitogen-activated protein kinase, FKS1, cell wall biosynthesis, stress signaling, genome-wide gene expression
MeSH terms: Caspofungin, Antifungal Agents, Cell Extracts, Cell Survival, Cells, Cultured, DNA-Binding Proteins, Drug Tolerance, Enzyme Activation, Fungal Proteins, Genes, Fungal, Kinetics, Models, Biological, Peptides, Peptides, Cyclic, Phosphorylation, Protein Kinase C, Repressor Proteins, RNA, Messenger, Saccharomyces cerevisiae, Signal Transduction, Down-Regulation, Gene Expression, Oligonucleotide Array Sequence Analysis, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Saccharomyces cerevisiae Proteins, Echinocandins, Lipopeptides

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The yeast protein kinase C cell integrity pathway mediates tolerance to the antifungal drug caspofungin through activation of Slt2p mitogen-activated protein kinase signaling.

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