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Eukaryotic Cell, December 2003, p. 1200-1210, Vol. 2, No. 6
1535-9778/03/$08.00+0     DOI: 10.1128/EC.2.6.1200-1210.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Yeast Protein Kinase C Cell Integrity Pathway Mediates Tolerance to the Antifungal Drug Caspofungin through Activation of Slt2p Mitogen-Activated Protein Kinase Signaling{dagger}

Cristina Reinoso-Martín, Christoph Schüller,* Manuela Schuetzer-Muehlbauer, and Karl Kuchler*

Department of Medical Biochemistry, Division of Molecular Genetics, Max F. Perutz Laboratories, University and Biocenter of Vienna, A-1030 Vienna, Austria

Received 11 August 2003/ Accepted 2 October 2003

The echinocandin caspofungin is a new antifungal drug that blocks cell wall synthesis through inhibition of ß-(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.

* Corresponding authors. Mailing address: Department of Medical Biochemistry, Division of Molecular Genetics, Max F. Perutz University Laboratories, Campus Vienna BioCenter, Dr. Bohr-Gasse 9/2, A-1030 Vienna, Austria. Phone: 43-1-4277-61807. Fax: 43-1-4277-9618. E-mail for K. Kuchler: karl.kuchler{at}univie.ac.at. E-mail for C. Schüller: christoph{at}mol.univie.ac.at.

{dagger} The supplemental material for this article may be found at http://ec.asm.org/.

Eukaryotic Cell, December 2003, p. 1200-1210, Vol. 2, No. 6
1535-9778/03/$08.00+0     DOI: 10.1128/EC.2.6.1200-1210.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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