Journal
NATURE
Volume 538, Issue 7625, Pages 350-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature19799
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Funding
- National Institutes of Health (NIH) [R01NS080833, R01AI091786, R01AT006732, R01DK084056, R01CA095287, K99DK100539, R01GM057603, R01GM074241, R01AR060359]
- Bill and Melinda Gates Foundation
- Timothy Murphy Fund
- Harvard Digestive Diseases Center [NIH P30DK034854]
- Boston Children's Hospital Intellectual and Developmental Disabilities Research Center [NIH P30HD18655]
- Burroughs Wellcome Fund
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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.
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