The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris.
Candida auris, an emerging fungal pathogen characterized by its multidrug resistance and high mortality rates, poses a significant public health challenge. Despite its importance, the signaling pathways governing virulence and antifungal resistance in C. auris remain poorly understood. This study in...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1013363 |
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| author | Hyunjin Cha Doyeon Won Seun Kang Eui-Seong Kim Kyung-Ah Lee Won-Jae Lee Kyung-Tae Lee Yong-Sun Bahn |
| author_facet | Hyunjin Cha Doyeon Won Seun Kang Eui-Seong Kim Kyung-Ah Lee Won-Jae Lee Kyung-Tae Lee Yong-Sun Bahn |
| author_sort | Hyunjin Cha |
| collection | DOAJ |
| description | Candida auris, an emerging fungal pathogen characterized by its multidrug resistance and high mortality rates, poses a significant public health challenge. Despite its importance, the signaling pathways governing virulence and antifungal resistance in C. auris remain poorly understood. This study investigates the calcineurin pathway in C. auris, critical for virulence and antifungal resistance in other fungal pathogens. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, comprises a catalytic subunit (Cna1) and a regulatory subunit (Cnb1) in C. auris. Our findings reveal that deletion of CNA1 or CNB1 disrupts extreme thermotolerance and cell membrane and wall integrity, leading to increased susceptibility to azoles and echinocandins. Moreover, we identified a downstream transcription factor, Crz1, which plays a central role in this pathway in other fungal species. Deletion of CRZ1 resulted in thermotolerance and membrane integrity defects comparable to those of cna1Δ and cnb1Δ mutants, along with increased azole susceptibility. Supporting it, fluconazole treatment induced Crz1 nuclear translocation in a Cna1-dependent manner. However, unlike cna1Δ and cnb1Δ mutants, the crz1Δ mutant displayed increased resistance to echinocandins, suggesting the opposing roles for Crz1 in regulating cell wall integrity. Nevertheless, echinocandins also promoted Crz1 nuclear translocation via Cna1, underscoring the complex regulatory mechanisms at play. Cna1 was found to be required for virulence in both the Drosophila systemic infection model and the murine skin infection model. However, in a systemic murine infection model, both calcineurin and Crz1 appeared dispensable for C. auris virulence. Our findings highlight that the evolutionarily conserved calcineurin pathway employs distinct regulatory mechanisms to perform divergent roles in regulating extreme thermotolerance, cell wall and membrane integrity, antifungal drug resistance, and virulence in C. auris. |
| format | Article |
| id | doaj-art-2892f2186e914aa6a38b8799d2e72ac1 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-2892f2186e914aa6a38b8799d2e72ac12025-08-20T03:59:35ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-07-01217e101336310.1371/journal.ppat.1013363The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris.Hyunjin ChaDoyeon WonSeun KangEui-Seong KimKyung-Ah LeeWon-Jae LeeKyung-Tae LeeYong-Sun BahnCandida auris, an emerging fungal pathogen characterized by its multidrug resistance and high mortality rates, poses a significant public health challenge. Despite its importance, the signaling pathways governing virulence and antifungal resistance in C. auris remain poorly understood. This study investigates the calcineurin pathway in C. auris, critical for virulence and antifungal resistance in other fungal pathogens. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, comprises a catalytic subunit (Cna1) and a regulatory subunit (Cnb1) in C. auris. Our findings reveal that deletion of CNA1 or CNB1 disrupts extreme thermotolerance and cell membrane and wall integrity, leading to increased susceptibility to azoles and echinocandins. Moreover, we identified a downstream transcription factor, Crz1, which plays a central role in this pathway in other fungal species. Deletion of CRZ1 resulted in thermotolerance and membrane integrity defects comparable to those of cna1Δ and cnb1Δ mutants, along with increased azole susceptibility. Supporting it, fluconazole treatment induced Crz1 nuclear translocation in a Cna1-dependent manner. However, unlike cna1Δ and cnb1Δ mutants, the crz1Δ mutant displayed increased resistance to echinocandins, suggesting the opposing roles for Crz1 in regulating cell wall integrity. Nevertheless, echinocandins also promoted Crz1 nuclear translocation via Cna1, underscoring the complex regulatory mechanisms at play. Cna1 was found to be required for virulence in both the Drosophila systemic infection model and the murine skin infection model. However, in a systemic murine infection model, both calcineurin and Crz1 appeared dispensable for C. auris virulence. Our findings highlight that the evolutionarily conserved calcineurin pathway employs distinct regulatory mechanisms to perform divergent roles in regulating extreme thermotolerance, cell wall and membrane integrity, antifungal drug resistance, and virulence in C. auris.https://doi.org/10.1371/journal.ppat.1013363 |
| spellingShingle | Hyunjin Cha Doyeon Won Seun Kang Eui-Seong Kim Kyung-Ah Lee Won-Jae Lee Kyung-Tae Lee Yong-Sun Bahn The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris. PLoS Pathogens |
| title | The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris. |
| title_full | The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris. |
| title_fullStr | The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris. |
| title_full_unstemmed | The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris. |
| title_short | The calcineurin pathway regulates extreme thermotolerance, cell membrane and wall integrity, antifungal resistance, and virulence in Candida auris. |
| title_sort | calcineurin pathway regulates extreme thermotolerance cell membrane and wall integrity antifungal resistance and virulence in candida auris |
| url | https://doi.org/10.1371/journal.ppat.1013363 |
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