Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway
ABSTRACT Candida albicans, the most frequently isolated fungal pathogen in humans, forms biofilms that enhance resistance to antifungal drugs and host immunity, leading to frequent treatment failure. Understanding the molecular mechanisms governing biofilm formation is crucial for developing anti-bi...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2025-02-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03283-24 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832096528212164608 |
|---|---|
| author | Li Mei Pang Guisheng Zeng Eve Wai Ling Chow Xiaoli Xu Ning Li Yee Jiun Kok Shu Chen Chong Xuezhi Bi Jiaxin Gao Chaminda Jayampath Seneviratne Yue Wang |
| author_facet | Li Mei Pang Guisheng Zeng Eve Wai Ling Chow Xiaoli Xu Ning Li Yee Jiun Kok Shu Chen Chong Xuezhi Bi Jiaxin Gao Chaminda Jayampath Seneviratne Yue Wang |
| author_sort | Li Mei Pang |
| collection | DOAJ |
| description | ABSTRACT Candida albicans, the most frequently isolated fungal pathogen in humans, forms biofilms that enhance resistance to antifungal drugs and host immunity, leading to frequent treatment failure. Understanding the molecular mechanisms governing biofilm formation is crucial for developing anti-biofilm therapies. In this study, we conducted a genetic screen to identify novel genes that regulate biofilm formation in C. albicans. One identified gene is ORF19.6693, a homolog of the Saccharomyces cerevisiae SDD3 gene. The sdd3∆/∆ mutant exhibited severe defects in biofilm formation and significantly reduced chitin content in the cell wall. Overexpression of the constitutively active version of the Rho1 GTPase Rho1G18V, an upstream activator of the protein kinase C (PKC)-mitogen-activated protein kinase (MAPK) cell-wall integrity pathway, rescued these defects. Affinity purification, mass spectrometry, and co-immunoprecipitation revealed Sdd3’s physical interaction with Bem2, the GTPase-activating protein of Rho1. Deletion of SDD3 significantly reduced the amount of the active GTP-bound form of Rho1, thereby diminishing PKC-MAPK signaling and downregulating chitin synthase genes CHS2 and CHS8. Taken together, our studies identify a new biofilm regulator, Sdd3, in C. albicans that modulates Rho1 activity through its inhibitory interaction with Bem2, thereby regulating the PKC-MAPK pathway to control chitin biosynthesis, which is critical for biofilm formation. As an upstream component of the pathway and lacking a homolog in mammals, Sdd3 has the potential to serve as an antifungal target for biofilm infections.IMPORTANCEThe human fungal pathogen Candida albicans is categorized as a critical priority pathogen on the World Health Organization’s Fungal Priority Pathogens List. A key virulence attribute of this pathogen is its ability to form biofilms on the surfaces of indwelling medical devices. Fungal cells in biofilms are highly resistant to antifungal drugs and host immunity, leading to treatment failure. This study conducted a genetic screen to discover novel genes that regulate biofilm formation. We found that deletion of the SDD3 gene caused severe biofilm defects. Sdd3 negatively regulates the Rho1 GTPase, an upstream activator of the protein kinase C-mitogen-activated protein kinase pathway, through direct interaction with Bem2, the GTPase-activating protein of Rho1, resulting in a significant decrease in chitin content in the fungal cell wall. This chitin synthesis defect leads to biofilm formation failure. Given its essential role in biofilm formation, Sdd3 could serve as an antifungal target for biofilm infections. |
| format | Article |
| id | doaj-art-9897b267539a4ca98b7780935f86cf5a |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-9897b267539a4ca98b7780935f86cf5a2025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03283-24Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathwayLi Mei Pang0Guisheng Zeng1Eve Wai Ling Chow2Xiaoli Xu3Ning Li4Yee Jiun Kok5Shu Chen Chong6Xuezhi Bi7Jiaxin Gao8Chaminda Jayampath Seneviratne9Yue Wang10A*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeBioprocessing Technology Institute, Singapore, SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeBioprocessing Technology Institute, Singapore, SingaporeState Key Laboratory of Mycology, Institute of Microbiology, Beijing, ChinaSingapore Oral Microbiomics Initiative, National Dental Research Institute Singapore, National Dental Center Singapore, Singapore, SingaporeA*STAR Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, SingaporeABSTRACT Candida albicans, the most frequently isolated fungal pathogen in humans, forms biofilms that enhance resistance to antifungal drugs and host immunity, leading to frequent treatment failure. Understanding the molecular mechanisms governing biofilm formation is crucial for developing anti-biofilm therapies. In this study, we conducted a genetic screen to identify novel genes that regulate biofilm formation in C. albicans. One identified gene is ORF19.6693, a homolog of the Saccharomyces cerevisiae SDD3 gene. The sdd3∆/∆ mutant exhibited severe defects in biofilm formation and significantly reduced chitin content in the cell wall. Overexpression of the constitutively active version of the Rho1 GTPase Rho1G18V, an upstream activator of the protein kinase C (PKC)-mitogen-activated protein kinase (MAPK) cell-wall integrity pathway, rescued these defects. Affinity purification, mass spectrometry, and co-immunoprecipitation revealed Sdd3’s physical interaction with Bem2, the GTPase-activating protein of Rho1. Deletion of SDD3 significantly reduced the amount of the active GTP-bound form of Rho1, thereby diminishing PKC-MAPK signaling and downregulating chitin synthase genes CHS2 and CHS8. Taken together, our studies identify a new biofilm regulator, Sdd3, in C. albicans that modulates Rho1 activity through its inhibitory interaction with Bem2, thereby regulating the PKC-MAPK pathway to control chitin biosynthesis, which is critical for biofilm formation. As an upstream component of the pathway and lacking a homolog in mammals, Sdd3 has the potential to serve as an antifungal target for biofilm infections.IMPORTANCEThe human fungal pathogen Candida albicans is categorized as a critical priority pathogen on the World Health Organization’s Fungal Priority Pathogens List. A key virulence attribute of this pathogen is its ability to form biofilms on the surfaces of indwelling medical devices. Fungal cells in biofilms are highly resistant to antifungal drugs and host immunity, leading to treatment failure. This study conducted a genetic screen to discover novel genes that regulate biofilm formation. We found that deletion of the SDD3 gene caused severe biofilm defects. Sdd3 negatively regulates the Rho1 GTPase, an upstream activator of the protein kinase C-mitogen-activated protein kinase pathway, through direct interaction with Bem2, the GTPase-activating protein of Rho1, resulting in a significant decrease in chitin content in the fungal cell wall. This chitin synthesis defect leads to biofilm formation failure. Given its essential role in biofilm formation, Sdd3 could serve as an antifungal target for biofilm infections.https://journals.asm.org/doi/10.1128/mbio.03283-24C. albicansbiofilmSDD3PKC-MAPK pathwaychitinfungal cell wall |
| spellingShingle | Li Mei Pang Guisheng Zeng Eve Wai Ling Chow Xiaoli Xu Ning Li Yee Jiun Kok Shu Chen Chong Xuezhi Bi Jiaxin Gao Chaminda Jayampath Seneviratne Yue Wang Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway mBio C. albicans biofilm SDD3 PKC-MAPK pathway chitin fungal cell wall |
| title | Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway |
| title_full | Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway |
| title_fullStr | Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway |
| title_full_unstemmed | Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway |
| title_short | Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway |
| title_sort | sdd3 regulates the biofilm formation of candida albicans via the rho1 pkc mapk pathway |
| topic | C. albicans biofilm SDD3 PKC-MAPK pathway chitin fungal cell wall |
| url | https://journals.asm.org/doi/10.1128/mbio.03283-24 |
| work_keys_str_mv | AT limeipang sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT guishengzeng sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT evewailingchow sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT xiaolixu sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT ningli sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT yeejiunkok sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT shuchenchong sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT xuezhibi sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT jiaxingao sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT chamindajayampathseneviratne sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway AT yuewang sdd3regulatesthebiofilmformationofcandidaalbicansviatherho1pkcmapkpathway |