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

被引：0

作者：

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

机构：

[1] Boston Children’s Hospital,Department of Urology

[2] Harvard Medical School,Department of Microbiology and Immunobiology and Department of Surgery

[3] Harvard Medical School,Department of Microbiology and Physiological Systems (MaPS)

[4] University of Massachusetts Medical School,Division of Endocrinology

[5] Boston Children’s Hospital,Department of Neurology

[6] Center for Infectious and Inflammatory Diseases,Department of Pediatrics

[7] Texas A & M Health Science Center,Gastroenterology Division, Department of Medicine

[8] Institute of Toxicology,undefined

[9] Hannover Medical School,undefined

[10] The F. M. Kirby Neurobiology Center,undefined

[11] Boston Children’s Hospital,undefined

[12] Harvard Medical School,undefined

[13] Harvard Medical School,undefined

[14] Tumor Microenvironment and Cancer Immunology Program,undefined

[15] Sanford-Burnham Prebys Medical Discovery Institute,undefined

[16] Cancer Center,undefined

[17] Harvard Medical School,undefined

[18] Harvard Stem Cell Institute,undefined

[19] University of Massachusetts Medical School,undefined

来源：

Nature | 2016年 / 538卷

关键词：

D O I：

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中图分类号：

学科分类号：

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.

引用

页码：350 / 355

页数：5

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