Protocadherin 20 maintains intestinal barrier function to protect against Crohn’s disease by targeting ATF6

Abstract

Background Intestinal barrier dysfunction plays a central role in the pathological onset of Crohn’s disease. We identify the cadherin superfamily member protocadherin 20 (PCDH20) as a crucial factor in Crohn’s disease. Here we describe the function of PCDH20 and its mechanisms in gut homeostasis, barrier integrity, and Crohn’s disease development. Results PCDH20 mRNA and protein expression is significantly downregulated in the colonic epithelium of Crohn’s disease patients and mice with induced colitis compared with controls. In mice, intestinal-specific Pcdh20 knockout causes defects in enterocyte proliferation and differentiation, while causing morphological abnormalities. Specifically, the deletion disrupts barrier integrity by unzipping adherens junctions via β-catenin regulation and p120-catenin phosphorylation, thus aggravating colitis in DSS- and TNBS-induced colitis mouse models. Furthermore, we identify activating transcription factor 6 (ATF6), a key chaperone of endoplasmic reticulum stress, as a functional downstream effector of PCDH20. By administering a selective ATF6 activator, the impairment of intestinal barrier integrity and dysregulation of CHOP/β-catenin/p-p120-catenin pathway was reversed in Pcdh20-ablated mice with colitis and PCDH20-deficient colonic cell lines. Conclusions PCDH20 is an essential factor in maintaining intestinal epithelial homeostasis and barrier integrity. Specifically, PCDH20 helps to protect against colitis by tightening adherens junctions through the ATF6/CHOP/β-catenin/p-p120-catenin axis.

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“…Endoplasmic reticulum stress and the dysregulation of the unfolded protein response have been implicated in the development of IBD, which are essential for the maintenance of homeostasis in both the intestine and immune cells (37, 38). Furthermore, the specific enrichment of Reactome pathway ATF6 alpha activates chaperone genes in CD is supported by evidence of that diminished ATF6 activity can contribute to intestinal barrier dysfunction in mouse models of IBD (39).…”

Identification of colon cancer subtypes based on multi-omics data—construction of methylation markers for immunotherapy

“…Notably, PCDH20 plays a crucial role in maintaining the balance and structural integrity of the intestinal epithelium. A decrease in the expression level of PCDH20 can disrupt the integrity of the intestinal mucosa, which can contribute to the development of colitis and Crohn’s disease ( 48 ). APCDD1 (adenomatosis polyposis down-regulated 1), a negative regulator of Wnt/β-catenin pathway, its expression was regulated by promotor methylation ( 49 ).…”