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

Yi-Cheng Ma,Cheng-Gang Zou,Zhong-Shan Yang,Ran Shu,Ke-Qin Zhang,Lan-Qing Ma,Read Pukkila-Worley

doi:10.1371/journal.ppat.1008766

Abstract

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.

Highlights

The intestinal epithelium forms a physical barrier to limit entry of pathogens, microbial antigens, and toxins from the luminal environment into the mucosal tissues [1,2,3]
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
To clarify the mechanisms of innate immune responses mediated by epithelial barrier disruption, we used RNA-Seq analysis to study the transcriptional profiles of worms at 24 hours after P. aeruginosa PA14 infection versus worms fed E. coli OP50

Summary

Introduction

The intestinal epithelium forms a physical barrier to limit entry of pathogens, microbial antigens, and toxins from the luminal environment into the mucosal tissues [1,2,3]. The epithelial barrier function is regulated by an apical junctional complex, consisting of the apical tight junctions (TJs), the subjacent adherens junctions (AJs), and the underlying desmosomes [3, 4]. AJs are composed of a cadherin (E-cadherin)-catenin complex and its associated proteins [4, 5]. The cytoplasmic tail of E-cadherin interacts with the Armadillo repeat protein β-catenin, which in turn binds α-catenin. TJs and AJs link epithelial cells to form an extremely effective barrier to macromolecules and bacteria [6]

Methods

Results

Conclusion