Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease.

Barun Das,Ronald R Marchelletta,Maho Niwa,John Rabalais,Kim E Barrett,Soumita Das,Kevin Okamoto,Mamata Sivagnanam

doi:10.3390/cells9040946

Barun Das, Ronald R Marchelletta + Show 6 more

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https://doi.org/10.3390/cells9040946

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Abstract

Congenital tufting enteropathy (CTE) is a rare chronic diarrheal disease of infancy caused by mutations in epithelial cell adhesion molecule (EpCAM). Previously, a murine CTE model showed mis-localization of EpCAM away from the basolateral cell surface in the intestine. Here we demonstrate that mutant EpCAM accumulated in the endoplasmic reticulum (ER) where it co-localized with ER chaperone, GRP78/BiP, revealing potential involvement of ER stress-induced unfolded protein response (UPR) pathway in CTE. To investigate the significance of ER-localized mutant EpCAM in CTE, activation of the three UPR signaling branches initiated by the ER transmembrane protein components IRE1, PERK, and ATF6 was tested. A significant reduction in BLOS1 and SCARA3 mRNA levels in EpCAM mutant intestinal cells demonstrated that regulated IRE1-dependent decay (RIDD) was activated. However, IRE1 dependent XBP1 mRNA splicing was not induced. Furthermore, an increase in nuclear-localized ATF6 in mutant intestinal tissues revealed activation of the ATF6-signaling arm. Finally, an increase in both the phosphorylated form of the translation initiation factor, eIF2α, and ATF4 expression in the mutant intestine provided support for activation of the PERK-mediated pathway. Our results are consistent with a significant role for UPR in gastrointestinal homeostasis and provide a working model for CTE pathophysiology.

Highlights

Congenital tufting enteropathy (CTE) belongs to a family of congenital diarrhea and enteropathies that cause persistent and severe diarrhea in infants and often lead to life-threatening intestinal failure.It is characterized by partial villous atrophy, crypt hyperplasia, and focal “tufts” of enterocytes of the intestinal epithelium [1,2]
We reported that mice expressing mutant epithelial cell adhesion molecule (EpCAM) recapitulated the disease phenotype, including the pathology of the intestinal epithelium [9]
Mutant EpCAM was no longer expressed on the cell surface in the epithelial cells of neonatal mutant mice, consistent with our previous study (Figure 1A lower panel) [9]

Summary

Introduction

Congenital tufting enteropathy (CTE) belongs to a family of congenital diarrhea and enteropathies that cause persistent and severe diarrhea in infants and often lead to life-threatening intestinal failure. It is characterized by partial villous atrophy, crypt hyperplasia, and focal “tufts” of enterocytes of the intestinal epithelium [1,2]. Most patients with CTE depend on parenteral nutrition and no direct treatments are currently available for the management of this disease. Mutations in EPCAM (Epithelial Cell Adhesion Molecule; known as CD326, GA773-2, TACSTD1, KSA, and TROP-1) were identified as causative in CTE [3].

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