2. Academic Validation
  3. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B

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

  • Nature. 2016 Oct 20;538(7625):350-355. doi: 10.1038/nature19799.
Liang Tao 1 2,  Jie Zhang 1 2,  Paul Meraner 3,  Alessio Tovaglieri 4,  Xiaoqian Wu 5,  Ralf Gerhard 6,  Xinjun Zhang 7 8,  William B Stallcup 9,  Ji Miao 4 10,  Xi He 7 8,  Julian G Hurdle 5,  David T Breault 4 10 11,  Abraham L Brass 3 12,  Min Dong 1 2
Affiliations

Affiliations

  • 1 Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 2 Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 3 Department of Microbiology and Physiological Systems (MaPS), University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  • 4 Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 5 Center for Infectious and Inflammatory Diseases, Texas A &M Health Science Center, Houston, Texas 77030, USA.
  • 6 Institute of Toxicology, Hannover Medical School, 30625 Hannover, Germany.
  • 7 The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 8 Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 9 Tumor Microenvironment and Cancer Immunology Program, Sanford-Burnham Prebys Medical Discovery Institute, Cancer Center, La Jolla, California 92037, USA.
  • 10 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 11 Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
  • 12 Gastroenterology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
PMID: 27680706 DOI: 10.1038/nature19799
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.

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