DUSP16 IS A NOVEL IBD GENE IMPLICATED IN THE REGULATION OF DIFFERENTIATION AND HOMEOSTASIS OF INTESTINAL EPITHELIAL CELLS

Abstract

Inflammatory bowel disease (IBD) are chronic inflammatory diseases including Crohn’s disease (CD) and ulcerative colitis (UC). More than 200 genomic regions have been identified and validated (association values (5x10-8) to be associated with CD, UC or IBD. These regions may contain multiple genes and the current challenge lies in identifying the causal gene in each of these. To address this problem, we performed a functional genomic screen of 145 genes from validated IBD loci, in a relevant intestinal epithelial cell model (HT-29). The results of this transcriptome-based screening revealed that the candidate IBD gene DUSP16 (a dual specificity phosphatase targeting MAP kinases (MAPKs) phosphorylation) as well as the known IBD gene KSR1 (a scaffold protein regulating the spatiotemporal activation of the ERK) regulate the expression of genes involved in intestinal differentiation and homeostasis. They induce, among others, the expression of the PIGR gene that encodes the polymeric immunoglobulin receptor. PIGR plays a role in transporting dimeric IgA molecules from the basolateral membrane of epithelial cells to the intestinal lumen, via transcytosis, where they play an essential role in protecting the epithelium against intestinal pathogens. Our hypothesis is that DUSP16 and KSR1 modulate the activity of MAPKs in intestinal epithelial cells to induce PIGR expression, thus participating in the maintenance of homeostasis of the intestinal barrier.