YAP in epithelium senses gut barrier loss to deploy defenses against pathogens.

Pathogens commonly disrupt the intestinal epithelial barrier; however, how the epithelial immune system senses the loss of intestinal barrier as a danger signal to activate self-defense is unclear. Through an unbiased approach in the model nematode Caenorhabditis elegans, we found that the EGL-44/TEAD transcription factor and its transcriptional activator YAP-1/YAP (Yes-associated protein) were activated when the intestinal barrier was disrupted by infections with the pathogenic bacterium Pseudomonas aeruginosa PA14. Gene Ontology enrichment analysis of the genes containing the TEAD-binding sites revealed that "innate immune response" and "defense response to Gram-negative bacterium" were two top significantly overrepresented terms. Genetic inactivation of yap-1 and egl-44 significantly reduced the survival rate and promoted bacterial accumulation in worms after bacterial infections. Furthermore, we found that disturbance of the E-cadherin-based adherens junction triggered the nuclear translocation and activation of YAP-1/YAP in the gut of worms. Although YAP is a major downstream effector of the Hippo signaling, our study revealed that the activation of YAP-1/YAP was independent of the Hippo pathway during disruption of intestinal barrier. After screening 10 serine/threonine phosphatases, we identified that PP2A phosphatase was involved in the activation of YAP-1/YAP after intestinal barrier loss induced by bacterial infections. Additionally, our study demonstrated that the function of YAP was evolutionarily conserved in mice. Our study highlights how the intestinal epithelium recognizes the loss of the epithelial barrier as a danger signal to deploy defenses against pathogens, uncovering an immune surveillance program in the intestinal epithelium. Author summary: The intestinal epithelial barrier is an important line of defense against pathogenic bacteria infecting the intestine. Persistent bacterial infections can cause disruption of the intestinal barrier; however, how the epithelia immune system recognizes the loss of intestinal barrier as a danger signal to activate self-defense against pathogens is unclear. Using the nematode Caenorhabditis elegans as a model animal, we show that the EGL-44/TEAD transcription factor and its transcriptional activator YAP-1/YAP (Yes-associated protein) are activated when the intestinal barrier is disrupted by bacterial infections. Gene Ontology enrichment reveals that EGL-44/TEAD orchestrates a complex host response composed of innate immune response and defense response to Gram-negative bacteria. Furthermore, our data demonstrate that YAP-1/YAP and EGL-44/TEAD are required for resistance to infections with pathogenic bacteria when the intestinal barrier is disrupted in worms and mice. Our study reveals a novel strategy for the intestinal epithelium to sense danger through its internal architecture and initiate innate immunity. [ABSTRACT FROM AUTHOR]