Frizzled proteins are colonic epithelial receptors for C. difficile toxin B.
Frizzled proteins are colonic epithelial receptors for C. difficile toxin B.
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DOI：
10.1038/nature19799
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发表时间：
2016-10-20
期刊：
影响因子：
64.8
通讯作者：
Dong M
中科院分区：
文献类型：
--
作者：
Tao L;Zhang J;Meraner P;Tovaglieri A;Wu X;Gerhard R;Zhang X;Stallcup WB;Miao J;He X;Hurdle JG;Breault DT;Brass AL;Dong M
艰难梭菌毒素B （TcdB）是引起艰难梭菌感染（CDI）相关疾病的关键毒力因子。在这里，我们进行了CRISPR/ cas9介导的全基因组筛选，并确定了Wnt受体frzzled （FZDs）家族的成员为TcdB受体。TcdB结合到保守的wnt结合位点，即富含半胱氨酸结构域（CRD），与FZD1、2和7的亲和力最高。TcdB与Wnt竞争FZDs的结合，其结合阻断Wnt信号传导。FZD1/2/7三敲除（KO）细胞对TcdB具有高度耐药性，重组FZD2-CRD可阻止TcdB与结肠上皮的结合。从FZD7 KO小鼠培养的结肠类器官，结合FZD1和2的敲除，显示出对TcdB的抗性增加。FZD7 KO小鼠结肠上皮对tdbb诱导的组织损伤不敏感。这些发现表明FZDs是结肠上皮中与TcdB生理相关的受体。
Clostridium difficile toxin B (TcdB) is a critical virulence factor causing diseases associated with C. difficile infection (CDI). Here we carried out CRISPR/Cas9-mediated genome-wide screens and identified the members of the Wnt receptor Frizzled (FZDs) family as TcdB receptors. TcdB binds to the conserved Wnt-binding site known as the cysteine-rich domain (CRD), with the highest affinity toward FZD1, 2, and 7. TcdB competes with Wnt for binding to FZDs, and its binding blocks Wnt signaling. FZD1/2/7 triple-knockout (KO) cells are highly resistant to TcdB, and recombinant FZD2-CRD prevented TcdB binding to the colonic epithelium. Colonic organoids cultured from FZD7 KO mice, combined with knock-down of FZD1 and 2, showed increased resistance to TcdB. The colonic epithelium in FZD7 KO 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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影响因子：
64.5
作者：
Gujral TS;Chan M;Peshkin L;Sorger PK;Kirschner MW;MacBeath G
通讯作者：
MacBeath G
DOI：
10.1073/pnas.96.7.3546
发表时间：
1999-03-30
影响因子：
11.1
作者：
Hsieh, JC;Rattner, A;Nathans, J
通讯作者：
Nathans, J
DOI：
10.1073/pnas.0604725103
发表时间：
2006-09-19
影响因子：
11.1
作者：
Hamm, Elaine E.;Voth, Daniel E.;Ballard, Jimmy D.
通讯作者：
Ballard, Jimmy D.
影响因子：
64.8
作者：
JUST, I;SELZER, J;AKTORIES, K
通讯作者：
AKTORIES, K
影响因子：
3.6
作者：
Genisyuerek, Selda;Papatheodorou, Panagiotis;Aktories, Klaus
通讯作者：
Aktories, Klaus