E-cadherin-YAP In Epithelium Senses Gut Barrier Loss To Deploy Host Defenses Against Pathogens

The intestinal epithelium forms a physical barrier that is the body's first line of defense against pathogens.At the same time,intestinal epithelial cells have evolved a variety of ways to eliminate bacterial pathogens.Bacterial pathogens commonly disrupt the intestinal epithelial barrier.However,the mechanism by which the epithelium senses a breach of the intestinal barrier activating self-defense is unclear.In this study,an unbiased transcription factor analysis revealed a significant enrichment of the transcription factor EGL-44/TEAD binding site in the promoter region of the differential gene expression in worms subjected to bacterial infections.GO analysis showed that the group of genes was involved in innate immune responses in worms.Transcriptional regulation of target genes by EGL-44/TEAD requires activation of transcriptional cofactor YAP-1/YAP,which are the downstream molecules of the Hippo signaling.Our results demonstrated that YAP-1 was dephosphorylated and translocated from cytoplasm into the nucleus when the intestinal barrier was disrupted during bacterial infections,indicating that YP-1 was activated.Importantly,deletion of yap-1 and egl-44 significantly reduced the survival rate of worms,significantly reduced the expression of immune genes,and promoted bacterial accumulation in the gut of worms.Bacterial infections disturbed the distribution of the adhesion junction in the intestinal epithelial cells by reducing the protein levels of E-cadherin-catenin complex,leading to disassociation of the E-cadherin complex and YAP-1.Notably,YAP was also activated in murine intestine upon bacterial infections.Specific knockdown of Yap in the intestinal epithelium significantly increased the susceptibility of mice to bacteria,and the bacterial accumulation in several tissues of mice,such as lung,live,blood,and spleen.Interestingly,bacterial infections did not alter phosphorylation levels of WTS-1/LAST,the upstream protein kinase of YAP-1/YAP suggesting that the activation of YAP-1/YAP is indepent of the Hippo signaling.By screening serine/theronine phosphatases in worms,we found that the inactivation of PP2 A phosphatase could effectively inhibit the activation of YAP-1.The mechanism is conserved in mice.In addition,specific silencing of PP2 Ac in the intestinal epithelial cells of mice significantly reduced the survival rate and increased the bacterial accumulation in the different tissues.Our study highlights the mechanism by which the intestinal epithelial cells recognize epithelial barrier disruption as a danger signal to deploy defenses against pathogens,revealing an evolutionarily conserved immune surveillance mechanism in the intestinal epithelium.