Protease-activated receptor 2 signaling modulates susceptibility of colonic epithelium to injury through stabilization of YAP in vivo

Longmei He,Xinhua Zhao,Weiwei Li,Wenxiao Han,Hongying Wang,Yiming Ma

doi:10.1038/s41419-018-0995-x

Abstract

Hippo signaling plays critical roles in intestinal regeneration. However, the mechanisms which regulate its activity in vivo are largely unknown. We hypothesize that protease-activated receptor 2 (PAR2) signaling, which could be activated by trypsin, might affect YAP activity in the setting of tissue damage and regeneration. It is found that knockout of PAR2 severely aggravates the mucosal damage induced by dextran sodium sulfate (DSS) in mouse, which correlated with notable repression of YAP protein in colonic epithelial cells. Although the cytokine expression is reduced, the damage of colonic crypt is more severe after DSS-induced colitis in PAR2-/- mouse. In vitro, PAR2 activation causes the accumulation of YAP, while knockdown of PAR2 with shRNA dramatically represses the expression of YAP protein in different intestinal epithelial cell lines. Moreover, forced expression of YAP significantly reduces the production of reactive oxygen species (ROS) and the sensitivity to nitric oxide-induced apoptosis in PAR2-deficient condition. Further studies show that PAR2 signaling stabilizes YAP protein but independent of Lats. Nevertheless PAR2 activation increased the binding of YAP with protein phosphatase PP1. Inhibition of PP1 with specific siRNA blocked PAR2-induced dephosphorylation of YAP. Taken together, PAR2 signaling might modulate susceptibility of colonic epithelium to injury through stabilization of YAP.

Highlights

The precise control of organ size is crucial during animal development and tissue regeneration
The expression of Ly6a, a marker related to regenerating crypt[12], Fig. 1 protease-activated receptor 2 (PAR2) deficiency impairs colonic regeneration following dextran sodium sulfate (DSS)-induced injury in mouse. a Schematic overview of DSS-induced colitis model in mouse. b hematoxylin and eosin (H&E) staining of colon sections taken from the mice 2 (DSS + 2d) or 4 days (DSS + 4d) after the administration of DSS
We show that PAR2 signaling mediates colonic mucosal regeneration through the stabilization of YAP protein in DSS-induced colitis in mouse

Summary

Introduction

The precise control of organ size is crucial during animal development and tissue regeneration. The uncontrolled overgrowth of tissue results in the formation of tumors. Chronic inflammation is a repetitive process of damage and repair, and has been shown to promote carcinogenesis in different organs. Deregulation of tissue regeneration after tissue damage contributes to inflammation-related carcinogenesis. Understanding the mechanisms which control the regeneration is critical. In the gut, proteases play critical roles during the pathological processes of trauma, inflammation, and Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion