Journal
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
Volume 35, Issue 2, Pages -Publisher
WILEY
DOI: 10.1002/jbt.22652
Keywords
Clostridium difficile; TAZ; toxin A; toxin B; YAP
Categories
Funding
- National Natural Science Foundation of China [81874177, 81672517, 31771545, 81974060, 91749120]
- Program for Professor of Special Appointment (Young Eastern Scholar) at Shanghai Institutions of Higher Learning
- Shanghai Municipal Commission of Health and Family Planning Young Program [20154Y0203]
- Shanghai Pujiang Program [18PJ1407400]
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Toxins A and B of Clostridium difficile disrupt the Hippo pathway, leading to sequestration and inactivation of YAP and TAZ in colonic epithelial cells. Overexpression of YAP restores cell function and may serve as a potential therapeutic strategy for treating CDI.
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.
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