Crohn's Disease-Associated Adherent-Invasive Escherichia coli Manipulate Host Autophagy by Impairing SUMOylation.

Guillaume Dalmasso,Hang T.T Nguyen,Sébastien Massier,Tiphanie Faïs,Richard Bonnet,Nicolas Barnich,Julien Delmas

doi:10.3390/cells8010035

Abstract

The intestinal mucosa of Crohn’s disease (CD) patients is abnormally colonized with adherent-invasive Escherichia coli (AIEC) that are able to adhere to and to invade intestinal epithelial cells (IECs), to survive in macrophages, and to induce a pro-inflammatory response. AIEC persist in the intestine, and induce inflammation in CEABAC10 transgenic mice expressing human CAECAM6, the receptor for AIEC. SUMOylation is a eukaryotic-reversible post-translational modification, in which SUMO, an ubiquitin-like polypeptide, is covalently linked to target proteins. Here, we investigated the role of SUMOylation in host responses to AIEC infection. We found that infection with the AIEC LF82 reference strain markedly decreased the levels of SUMO-conjugated proteins in human intestinal epithelial T84 cells. This was also observed in IECs from LF82-infected CEABAC10 transgenic mice. LF82-induced deSUMOylation in IECs was due in part to increased level of microRNA (miR)-18, which targets PIAS3 mRNA encoding a protein involved in SUMOylation. Over-expression of SUMOs in T84 cells induced autophagy, leading to a significant decrease in the number of intracellular LF82. Consistently, a decreased expression of UBC9, a protein necessary for SUMOylation, was accompanied with a decrease of LF82-induced autophagy, increasing bacterial intracellular proliferation and inflammation. Finally, the inhibition of miR-18 significantly decreased the number of intracellular LF82. In conclusion, our results suggest that AIEC inhibits the autophagy response to replicate intracellularly by manipulating host SUMOylation.

Highlights

Inflammatory bowel diseases (IBD), which include ulcerative colitis and Crohn’s disease (CD), are chronic gastrointestinal disorders
To investigate whether adherent-invasive Escherichia coli (AIEC) are able to modify the SUMOylation of host cells, we compared the global pattern of SUMO1- or SUMO2/3-conjugated proteins in human intestinal epithelial T84 cells uninfected or infected with the AIEC LF82 reference strain
SUMOylation by AIEC infection, CEABAC10 transgenic mice expressing human carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), the host receptor required for AIEC adherence [7], were infected with LF82 or MG1655 bacteria by gavage, as previously described [8]

Summary

Introduction

Inflammatory bowel diseases (IBD), which include ulcerative colitis and Crohn’s disease (CD), are chronic gastrointestinal disorders. Extensive studies in the last few decades have shown that the etiology of IBD involves environmental and genetic factors that lead to the dysfunction of the epithelial barrier, with consequent deregulation of the mucosal immune response to gut microbiota [1]. AIEC have been shown to adhere to and to invade intestinal epithelial cells (IECs), to survive and replicate inside macrophages without inducing cell death, and to induce a high production of pro-inflammatory cytokines and chemiokines [2,3]. AIEC adhere to enterocytes via the interaction between type 1 pili and the host receptor carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which is abnormally expressed in the enterocytes from CD patients [7]

Methods

Results

Conclusion