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Paeniclostridium sordellii hemorrhagic toxin targets TMPRSS2 to induce colonic epithelial lesions

Author

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  • Xingxing Li

    (Fudan University
    Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Liuqing He

    (Fudan University
    Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Jianhua Luo

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Yangling Zheng

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Yao Zhou

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Danyang Li

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Yuanyuan Zhang

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Zhenrui Pan

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

  • Yanyan Li

    (Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou)

  • Liang Tao

    (Fudan University
    Westlake University
    Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou
    Institute of Basic Medical Sciences, Westlake Institute for Advanced Study)

Abstract

Hemorrhagic toxin (TcsH) is an important exotoxin produced by Paeniclostridium sordellii, but the exact role of TcsH in the pathogenesis remains unclear, partly due to the lack of knowledge of host receptor(s). Here, we carried out two genome-wide CRISPR/Cas9 screens parallelly with TcsH and identified cell surface fucosylation and TMPRSS2 as host factors contributing to the binding and entry of TcsH. Genetic deletion of either fucosylation biosynthesis enzymes or TMPRSS2 in the cells confers resistance to TcsH intoxication. Interestingly, TMPRSS2 and fucosylated glycans can mediate the binding/entry of TcsH independently, thus serving as redundant receptors. Both TMPRSS2 and fucosylation recognize TcsH through its CROPs domain. By using Tmprss2‒/‒ mice, we show that Tmprss2 is important for TcsH-induced systematic toxicity and colonic epithelial lesions. These findings reveal the importance of TMPRSS2 and surface fucosylation in TcsH actions and further provide insights into host recognition mechanisms for large clostridial toxins.

Suggested Citation

  • Xingxing Li & Liuqing He & Jianhua Luo & Yangling Zheng & Yao Zhou & Danyang Li & Yuanyuan Zhang & Zhenrui Pan & Yanyan Li & Liang Tao, 2022. "Paeniclostridium sordellii hemorrhagic toxin targets TMPRSS2 to induce colonic epithelial lesions," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31994-x
    DOI: 10.1038/s41467-022-31994-x
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    References listed on IDEAS

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    1. Peng Chen & Ji Zeng & Zheng Liu & Hatim Thaker & Siyu Wang & Songhai Tian & Jie Zhang & Liang Tao & Craig B. Gutierrez & Li Xing & Ralf Gerhard & Lan Huang & Min Dong & Rongsheng Jin, 2021. "Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Liang Tao & Jie Zhang & Paul Meraner & Alessio Tovaglieri & Xiaoqian Wu & Ralf Gerhard & Xinjun Zhang & William B. Stallcup & Ji Miao & Xi He & Julian G. Hurdle & David T. Breault & Abraham L. Brass &, 2016. "Frizzled proteins are colonic epithelial receptors for C. difficile toxin B," Nature, Nature, vol. 538(7625), pages 350-355, October.
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    Cited by:

    1. Ruoyu Zhou & Liuqing He & Jiahao Zhang & Xiaofeng Zhang & Yanyan Li & Xiechao Zhan & Liang Tao, 2024. "Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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