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Global fungal-host interactome mapping identifies host targets of candidalysin

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & R, 2024. "Global fungal-host interactome mapping identifies host targets of candidalysin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46141-x
    DOI: 10.1038/s41467-024-46141-x
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    References listed on IDEAS

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    1. Lydia Kasper & Annika König & Paul-Albert Koenig & Mark S. Gresnigt & Johannes Westman & Rebecca A. Drummond & Michail S. Lionakis & Olaf Groß & Jürgen Ruland & Julian R. Naglik & Bernhard Hube, 2018. "The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes," Nature Communications, Nature, vol. 9(1), pages 1-20, December.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Y. Erin Chen & Michael A. Fischbach & Yasmine Belkaid, 2018. "Erratum: Skin microbiota–host interactions," Nature, Nature, vol. 555(7697), pages 543-543, March.
    4. Y. Erin Chen & Michael A. Fischbach & Yasmine Belkaid, 2018. "Skin microbiota–host interactions," Nature, Nature, vol. 553(7689), pages 427-436, January.
    5. Yingyao Zhou & Bin Zhou & Lars Pache & Max Chang & Alireza Hadj Khodabakhshi & Olga Tanaseichuk & Christopher Benner & Sumit K. Chanda, 2019. "Metascape provides a biologist-oriented resource for the analysis of systems-level datasets," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    6. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    7. Jemima Ho & Xuexin Yang & Spyridoula-Angeliki Nikou & Nessim Kichik & Andrew Donkin & Nicole O. Ponde & Jonathan P. Richardson & Remi L. Gratacap & Linda S. Archambault & Christian P. Zwirner & Celia , 2019. "Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    8. Nadezda V. Volkova & Bettina Meier & Víctor González-Huici & Simone Bertolini & Santiago Gonzalez & Harald Vöhringer & Federico Abascal & Iñigo Martincorena & Peter J. Campbell & Anton Gartner & Morit, 2020. "Mutational signatures are jointly shaped by DNA damage and repair," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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