Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease
| Autor: | Maho Niwa, Barun Das, Kevin Okamoto, John Rabalais, Kim E. Barrett, Mamata Sivagnanam, Soumita Das, Ronald R. Marchelletta |
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| Rok vydání: | 2020 |
| Předmět: |
Diarrhea
Mutant Infantile Article Mice chemistry.chemical_compound congenital tufting enteropathy Malabsorption Syndromes Genetics medicine Animals Humans 2.1 Biological and endogenous factors Aetiology lcsh:QH301-705.5 Endoplasmic Reticulum Chaperone BiP Animal ATF6 Endoplasmic reticulum ATF4 Infant Newborn Infant mutant EpCAM Epithelial cell adhesion molecule unfolded protein response General Medicine Newborn Epithelial Cell Adhesion Molecule medicine.disease Congenital tufting enteropathy Transmembrane protein Cell biology Disease Models Animal lcsh:Biology (General) chemistry Diarrhea Infantile Disease Models Chronic Disease Unfolded protein response rnfolded protein response ER stress Digestive Diseases |
| Zdroj: | Cells, vol 9, iss 4 Cells Volume 9 Issue 4 Cells, Vol 9, Iss 946, p 946 (2020) |
| ISSN: | 2073-4409 |
| Popis: | 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, eIF2&alpha 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. |
| Databáze: | OpenAIRE |
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