Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
Open accessAbstract
Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diverse diseases, yet kinases remain untapped in the quest for new antifungals. Here, we performed a comprehensive analysis of the C. albicans kinome to identify genes for which loss-of-function confers hypersensitivity to the two most widely deployed antifungals, echinocandins and azoles. Through this analysis, we found a role for the casein kinase 1 (CK1) homologue Hrr25 in regulating tolerance to both antifungals as well as target-mediated echinocandin resistance. Follow-up investigations established that Hrr25 regulates these responses through its interaction with the SBF transcription factor. Thus, we provide insights into the circuitry governing cellular responses to antifungals and implicate Hrr25 as a key mediator of drug resistance.
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Hrr25 maintains cell wall homoeostasis by interacting with the SBF (Swi4/Swi6) transcription factor.
“Further mechanistic investigations determined that Hrr25 maintains cell wall homoeostasis by interacting with the SBF (Swi4/Swi6) transcription factor89.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [89]
Hrr25 is required for azole tolerance in a clinical isolate.
“Hrr25 was also demonstrated to be required for azole tolerance in a clinical isolate89.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [89]
CK1 family members Yck2 and Hrr25 are implicated in FKS1-mediated echinocandin resistance in C. albicans.
“More recently, the casein kinase 1 (CK1) family members, Yck2 and Hrr25, were implicated in FKS1-mediated echinocandin resistance in C. albicans88,89.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [89]
SBF is a well-characterized downstream effector of the PKC-MAPK cascade.
“Given that SBF is a well-characterized downstream effector of the PKC-MAPK cascade, this highlights the potential crosstalk between Hrr25 and Pkc1 signalling in regulating drug-induced stress responses78,89”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [89]
There is potential crosstalk between Hrr25 and Pkc1 signalling in regulating drug-induced stress responses.
“Given that SBF is a well-characterized downstream effector of the PKC-MAPK cascade, this highlights the potential crosstalk between Hrr25 and Pkc1 signalling in regulating drug-induced stress responses78,89”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [89]
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Molecular mechanisms governing antifungal drug resistance
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- Authors
- Lee, Y., Liston, S. D., Lee, D., Robbins, N., & Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Cowen, Leah E.
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 25
- Issue
- 6
- Pages
- 104432
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC9160768
- OpenAlex
- W4280539175
- Cited by
- 18
- References
- 65
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 3 · 2023: 3 · 2022: 1
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Merck
- Canadian Institute for Advanced Research
- National Institutes of Health
- Genome Canada
- Canadian Institutes of Health Research (FDN-154288)
- National Research Council Canada
- NIAID (R01AI127375, R01AI162789)
- Canada Research Chairs
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Candida albicans, kinome, casein kinase 1, antifungal resistance, echinocandin resistance, azole resistance, antifungal susceptibility, SBF transcription factor, protein kinases, antifungal drug targets
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