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Frizzled Proteins Are Colonic Epithelial Receptors for C. Difficile Toxin B

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, Min Dong

Nature. 2016 Oct 20;538(7625):350-355.

PMID: 27680706

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4242912	Clostridium difficile Toxin B			Price

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