Global fungal-host interactome mapping identifies host targets of candidalysin

Tian-Yi Zhang, Yao-Qi Chen, Jing-Cong Tan, Jin-An Zhou, Wan-Ning Chen, Tong Jiang, Jin-Yin Zha, Xiang-Kang Zeng, Bo-Wen Li, Lu-Qi Wei, Yun Zou, Lu-Yao Zhang, Yue-Mei Hong, Xiu-Li Wang, Run-Ze Zhu, Wan-Xing Xu, Jing Xi, Qin-Qin Wang, Lei Pan, Jian Zhang, Yang Luan, Rui-Xin Zhu, Hui Wang (), Changbin Chen () and Ning-Ning Liu ()
Additional contact information
Tian-Yi Zhang: Shanghai Jiao Tong University School of Medicine
Yao-Qi Chen: Shanghai Jiao Tong University School of Medicine
Jing-Cong Tan: Shanghai Jiao Tong University School of Medicine
Jin-An Zhou: Shanghai Jiao Tong University School of Medicine
Wan-Ning Chen: Tongji University
Tong Jiang: Chinese Academy of Sciences
Jin-Yin Zha: Shanghai Jiao Tong University, School of Medicine
Xiang-Kang Zeng: Chinese Academy of Science
Bo-Wen Li: Shanghai Jiao Tong University School of Medicine
Lu-Qi Wei: Shanghai Jiao Tong University School of Medicine
Yun Zou: Chinese Academy of Sciences
Lu-Yao Zhang: Chinese Academy of Sciences
Yue-Mei Hong: Shanghai Jiao Tong University School of Medicine
Xiu-Li Wang: Shanghai Jiao Tong University School of Medicine
Run-Ze Zhu: Shanghai Jiao Tong University School of Medicine
Wan-Xing Xu: Shanghai Jiao Tong University School of Medicine
Jing Xi: Shanghai Jiao Tong University School of Medicine
Qin-Qin Wang: Shanghai Jiao Tong University School of Medicine
Lei Pan: Chinese Academy of Science
Jian Zhang: Shanghai Jiao Tong University, School of Medicine
Yang Luan: Shanghai Jiao Tong University School of Medicine
Rui-Xin Zhu: Tongji University
Hui Wang: Shanghai Jiao Tong University School of Medicine
Changbin Chen: Chinese Academy of Sciences
Ning-Ning Liu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.

Date: 2024
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DOI: 10.1038/s41467-024-46141-x

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