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

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 and Min Dong ()
Additional contact information
Liang Tao: Boston Children’s Hospital, Harvard Medical School
Jie Zhang: Boston Children’s Hospital, 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
William B. Stallcup: Tumor Microenvironment and Cancer Immunology Program, Sanford-Burnham Prebys Medical Discovery Institute, Cancer Center
Ji Miao: Boston Children’s Hospital
Xi He: The F. M. Kirby Neurobiology Center, Boston Children’s Hospital, 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
Abraham L. Brass: University of Massachusetts Medical School
Min Dong: Boston Children’s Hospital, Harvard Medical School

Nature, 2016, vol. 538, issue 7625, 350-355

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19799

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