Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata: Role of the Slt2 MAPK pathway in C. glabrata
Open accessAbstract
The Slt2 mitogen-activated protein kinase pathway plays a major role in maintaining fungal cell wall integrity. In this study, we investigated the effects of SLT2 deletion and overexpression on drug susceptibility and virulence in the opportunistic fungal pathogen Candida glabrata. While the Deltaslt2 strain showed decreased tolerance to elevated temperature and cell wall-damaging agents, the SLT2-overexpressing strain exhibited increased tolerance to these stresses. A mutant lacking Rlm1, a transcription factor downstream of Slt2, displayed a cell wall-associated phenotype intermediate to that of the Deltaslt2 strain. When RLM1 was overexpressed, micafungin tolerance was increased in the wild-type strain and partial restoration of the drug tolerance was observed in the Deltaslt2 background. It was also demonstrated that echinocandin-class antifungals were more effective against C. glabrata under acidic conditions or when used concurrently with the chitin synthesis inhibitor nikkomycin Z. Finally, in a mouse model of disseminated candidiasis, the deletion and overexpression of C. glabrata SLT2 resulted in mild decreases and increases, respectively, in the CFUs from murine organs compared with the wild-type strain. These fundamental data will help in further understanding the mechanisms of cell wall stress response in C. glabrata and developing more effective treatments using echinocandin antifungals in clinical settings.
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In C. glabrata, both calcineurin and PKC signaling have been implicated in basal tolerance to echinocandins.
“In C. glabrata, both calcineurin and PKC signaling have been implicated in basal tolerance to echinocandins [48], [49], though the role of Hsp90 remains unknown as does the impact of any of these regulators on bona fide echinocandin resistance.”
From Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata (2012) · cites this paper as [48]
The protein kinase C (PKC)-mediated signaling pathway safeguards the cell wall in C. glabrata, and its terminal mitogen-activated protein kinase CgSlt2, along with other cascade components, is required for survival of cell wall stress.
“The protein kinase C (PKC)-mediated signaling pathway safeguards the cell wall in C. glabrata, and its terminal mitogen-activated protein kinase (MAPK) CgSlt2, along with other cascade components, is required for survival of the cell wall stress [54,90,91].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [90]
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- Authors
- Miyazaki, T., Inamine, T., Yamauchi, S., Nagayoshi, Y., Saijo, T., Izumikawa, K., Seki, M., Kakeya, H., Yamamoto, Y., Yanagihara, K., Miyazaki, Y., & Kohno, S.
- Affiliations
- Nagasaki University (JP)
- National Institute of Infectious Diseases (JP)
- Corresponding author
- Miyazaki, Taiga
- ORCID
- Venue
- FEMS Yeast Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04-12
- Volume
- 10
- Issue
- 3
- Pages
- 343-352
- ISSN
- 1567-1356 (ISSN-L)
- 1567-1364
- OpenAlex
- W2112557952
- Cited by
- 70
- References
- 45
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 1 · 2023: 3 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 9 · 2015: 4 · 2014: 7 · 2013: 8 · 2012: 4
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEMS Yeast Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Nagasaki University's Academic Output SITE (Nagasaki University) (submittedVersion, cc-by-nc-nd)
- Funders
- Ministry of Health, Labour and Welfare
- Japan Society for the Promotion of Science (19790324, 21390305)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida glabrata, cell wall integrity, virulence, drug sensitivity, echinocandins, nikkomycin Z, chitin synthesis inhibition, heat tolerance, systemic candidiasis, opportunistic fungal pathogens
- MeSH terms
- Aminoglycosides, Animals, Animal Structures, Antifungal Agents, Candidiasis, Cell Wall, Disease Models, Animal, Female, Fungal Proteins, Hot Temperature, Mice, Inbred BALB C, Stress, Physiological, Virulence, Colony Count, Microbial, Gene Deletion, Mitogen-Activated Protein Kinases, Virulence Factors, Candida glabrata, Mice, Echinocandins
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