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Frizzled proteins are colonic epithelial receptors for C. difficile toxin B

Author

Listed:
  • Liang Tao

    (Boston Children’s Hospital, Harvard Medical School
    Harvard Medical School)

  • Jie Zhang

    (Boston Children’s Hospital, Harvard Medical School
    Harvard Medical School)

  • Paul Meraner

    (University of Massachusetts Medical School)

  • Alessio Tovaglieri

    (Boston Children’s Hospital)

  • Xiaoqian Wu

    (Center for Infectious and Inflammatory Diseases, Texas A & M Health Science Center)

  • Ralf Gerhard

    (Institute of Toxicology, Hannover Medical School)

  • Xinjun Zhang

    (The F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
    Harvard Medical School)

  • William B. Stallcup

    (Tumor Microenvironment and Cancer Immunology Program, Sanford-Burnham Prebys Medical Discovery Institute, Cancer Center)

  • Ji Miao

    (Boston Children’s Hospital
    Harvard Medical School)

  • Xi He

    (The F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School
    Harvard Medical School)

  • Julian G. Hurdle

    (Center for Infectious and Inflammatory Diseases, Texas A & M Health Science Center)

  • David T. Breault

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Abraham L. Brass

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Min Dong

    (Boston Children’s Hospital, Harvard Medical School
    Harvard Medical School)

Abstract

Clostridium difficile toxin B (TcdB) is a critical virulence factor that causes diseases associated with C. difficile infection. Here we carried out CRISPR–Cas9-mediated genome-wide screens and identified the members of the Wnt receptor frizzled family (FZDs) as TcdB receptors. TcdB binds to the conserved Wnt-binding site known as the cysteine-rich domain (CRD), with the highest affinity towards FZD1, 2 and 7. TcdB competes with Wnt for binding to FZDs, and its binding blocks Wnt signalling. FZD1/2/7 triple-knockout cells are highly resistant to TcdB, and recombinant FZD2-CRD prevented TcdB binding to the colonic epithelium. Colonic organoids cultured from FZD7-knockout mice, combined with knockdown of FZD1 and 2, showed increased resistance to TcdB. The colonic epithelium in FZD7-knockout mice was less susceptible to TcdB-induced tissue damage in vivo. These findings establish FZDs as physiologically relevant receptors for TcdB in the colonic epithelium.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:538:y:2016:i:7625:d:10.1038_nature19799
    DOI: 10.1038/nature19799
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    Cited by:

    1. Alexander Belyy & Philipp Heilen & Philine Hagel & Oliver Hofnagel & Stefan Raunser, 2023. "Structure and activation mechanism of the Makes caterpillars floppy 1 toxin," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. 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.
    3. Songhai Tian & Xiaozhe Xiong & Ji Zeng & Siyu Wang & Benjamin Jean-Marie Tremblay & Peng Chen & Baohua Chen & Min Liu & Pengsheng Chen & Kuanwei Sheng & Daniel Zeve & Wanshu Qi & David T. Breault & Cé, 2022. "Identification of TFPI as a receptor reveals recombination-driven receptor switching in Clostridioides difficile toxin B variants," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Xinchen Lv & Yuanyuan Zhang & Ke Sun & Qi Yang & Jianhua Luo & Liang Tao & Peilong Lu, 2024. "De novo design of mini-protein binders broadly neutralizing Clostridioides difficile toxin B variants," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. 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.

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