Global fungal-host interactome mapping identifies host targets of candidalysin.

Autor: Zhang TY; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Chen YQ; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Tan JC; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Zhou JA; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Chen WN; Department of Gastroenterology, The Shanghai Tenth People's Hospital, Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China., Jiang T; The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Unit of Pathogenic Fungal Infection & Host Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China., Zha JY; State Key Laboratory of Systems Medicine for Cancer, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China., Zeng XK; The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Science, Shanghai, China., Li BW; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Wei LQ; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Zou Y; The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Unit of Pathogenic Fungal Infection & Host Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China., Zhang LY; The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Unit of Pathogenic Fungal Infection & Host Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China., Hong YM; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Wang XL; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Zhu RZ; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Xu WX; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Xi J; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Wang QQ; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Pan L; The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Science, Shanghai, China., Zhang J; State Key Laboratory of Systems Medicine for Cancer, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China., Luan Y; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China., Zhu RX; Department of Gastroenterology, The Shanghai Tenth People's Hospital, Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China., Wang H; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. huiwang@shsmu.edu.cn., Chen C; The Center for Microbes, Development, and Health, Key Laboratory of Molecular Virology and Immunology, Unit of Pathogenic Fungal Infection & Host Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, 200031, China. cbchen@siii.cas.cn., Liu NN; State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. liuningning@shsmu.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 27; Vol. 15 (1), pp. 1757. Date of Electronic Publication: 2024 Feb 27.
DOI: 10.1038/s41467-024-46141-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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