Toxin A (TcdA) and toxin B (TcdB), the two exotoxins of Clostridium difficile, are main causal agents for the colonic epithelium damage in Clostridium difficile infection (CDI). The Hippo pathway is crucial for the control of tissue homeostasis and regeneration of intestines. However, the dysregulation of Hippo pathway in CDI is unclear. Here we show that YAP and TAZ, the transcriptional coactivators downstream of the Hippo pathway, are sequestered in the cytoplasm, degraded, and inactivated by treatment with TcdA and TcdB in colonic epithelial cells. The overexpression of YAP restores the messenger RNA expressions of YAP target genes, attenuates the disruption of cytoskeleton and cell rounding, and rescues the cell proliferation of colonic epithelial cells under exposure of the two toxins. Our results demonstrate that inhibition of YAP and TAZ is involved in the pathogenesis of CDI, implicating that increasing YAP activity could be a potential therapeutic strategy for the CDI treatment.

中文翻译：

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艰难梭菌毒素A和毒素B抑制结肠上皮细胞中的YAP

艰难梭菌的两种外毒素毒素A（TcdA）和毒素B（TcdB）是造成艰难梭菌结肠上皮损伤的主要诱因感染（CDI）。河马途径对于控制组织稳态和肠道再生至关重要。但是，尚不清楚CDI中Hippo通路的失调。在这里，我们显示YAP和TAZ，河马途径下游的转录共激活因子，被隔离在细胞质中，通过在结肠上皮细胞中用TcdA和TcdB处理而降解和失活。YAP的过表达恢复了YAP靶基因的信使RNA表达，减弱了细胞骨架的破坏和细胞变圆，并在两种毒素暴露下拯救了结肠上皮细胞的细胞增殖。我们的结果表明，抑制YAP和TAZ参与CDI的发病机理，暗示增加的YAP活性可能是CDI治疗的潜在治疗策略。