Coordinated regulation of pH alkalinization by two transcription factors promotes fungal commensalism and pathogenicity

Xinhua Huang (), Guangsheng Chen, Lei Wu, Yun Zou, Luyao Zhang, Shanshan Li, Kunlin Li, Zaijie Jiang, Yuping Zhang, Xiaoqing Chen, Winnie Shum, Jianbiao Dai, Huichang Huang, Munika Moses, Xianwei Wu, Yuanyuan Wang, Tong Jiang, Zhiyi He, Qing Guo, Wenwen Xue, Hao Li () and Changbin Chen ()
Additional contact information
Xinhua Huang: Chinese Academy of Sciences
Guangsheng Chen: The First Affiliated Hospital of Guangxi Medical University
Lei Wu: Chinese Academy of Sciences
Yun Zou: Chinese Academy of Sciences
Luyao Zhang: Chinese Academy of Sciences
Shanshan Li: Chinese Academy of Sciences
Kunlin Li: Chinese Academy of Sciences
Zaijie Jiang: Chinese Academy of Sciences
Yuping Zhang: Chinese Academy of Sciences
Xiaoqing Chen: Chinese Academy of Sciences
Winnie Shum: University of Saint Joseph
Jianbiao Dai: University of Saint Joseph
Huichang Huang: Chinese Academy of Sciences
Munika Moses: Chinese Academy of Sciences
Xianwei Wu: Chinese Academy of Sciences
Yuanyuan Wang: Chinese Academy of Sciences
Tong Jiang: Chinese Academy of Sciences
Zhiyi He: The First Affiliated Hospital of Guangxi Medical University
Qing Guo: The Fourth Hospital of Shijiazhuang (Affiliated Obstetrics and Gynecology Hospital of Hebei Medical University)
Wenwen Xue: Nanjing Advanced Academy of Life and Health
Hao Li: Xiamen University
Changbin Chen: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract As a clinically relevant opportunistic human fungal pathogen, Candida albicans is able to rapidly sense and adapt to changing microenvironments within the host, a process that is essential for its successful invasion and survival. Although studies have shown that the transcription factor Stp2 is the master regulator of environmental alkalinization, accumulating evidence supports a clear involvement of other participants in this adaptation process. Here, following a large-scale genetic screen, we identify the transcription factor Dal81 as an uncharacterized positive regulator of pH alkalinization in C. albicans. Dal81 influences the protein levels of Stp2. A mutant lacking DAL81 also fails to alkalinize both in vitro and in the phagolysosome, and this defective phenotype is further enhanced by deleting both factors in most cases. Notably, our results demonstrate that Dal81 physically interacts with Stp2 to co-regulate the expression of a broad set of downstream target genes related to metabolism of organic acids, oxoacids, carboxylic acids and amino acids. This coordinated regulation mode is required for the alkalinization process and plays a role in modulating commensalism and pathogenicity of C. albicans. Taken together, our findings elucidate the cooperative function of Dal81 with Stp2 in the nucleus to orchestrate the expression of downstream genes required for the survival and propagation of C. albicans in the host.

Date: 2025
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DOI: 10.1038/s41467-025-62953-x

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