Frizzled proteins are colonic epithelial receptors for C. difficile toxin B | |
Article | |
关键词: UDP-GLUCOSE DEFICIENCY; CLOSTRIDIUM-DIFFICILE; STEM-CELLS; IN-VITRO; INFECTION; MODEL; IDENTIFICATION; TRANSLOCATION; EXPRESSION; VIRULENCE; | |
DOI : 10.1038/nature19799 | |
来源: SCIE |
【 摘 要 】
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.
【 授权许可】
Free