Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway

Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway

mBio

10.1128/mbio.03283-24

https://doi.org/10.1128/mbio.03283-24

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

Cell Biology, Molecular Biology

17 December 2024

Pang, L. M., Zeng, G., Chow, E. W. L., Xu, X., Li, N., Kok, Y. J., Chong, S. C., Bi, X., Gao, J., Seneviratne, C. J., & Wang, Y. (2025). Sdd3 regulates the biofilm formation of Candida albicans via the Rho1-PKC-MAPK pathway. MBio, 16(2). https://doi.org/10.1128/mbio.03283-24

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Medical Research Council of Singapore - Open Fund - Individual Research Grant
Grant Reference no. : OFIRG/0072/2018

Khoo Postdoctoral Fellowship Award (Duke-NUS-KPFA/2020/0043) from the Estate of Tan Sri Khoo Teck Puat, Singapore to L.M.P.

https://oar.a-star.edu.sg/communities-collections/articles/22249

2150-7511

A*STAR Infectious Disease Labs