Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease
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 muta...
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MDPI AG
2020-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/4/946 |
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| author | Barun Das Kevin Okamoto John Rabalais Ronald R. Marchelletta Kim E. Barrett Soumita Das Maho Niwa Mamata Sivagnanam |
| author_facet | Barun Das Kevin Okamoto John Rabalais Ronald R. Marchelletta Kim E. Barrett Soumita Das Maho Niwa Mamata Sivagnanam |
| author_sort | Barun Das |
| collection | DOAJ |
| description | 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 <i>XBP1</i> 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. |
| first_indexed | 2024-03-10T20:30:49Z |
| format | Article |
| id | doaj.art-3dbb270ff7f54b17916142b6701171e3 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:30:49Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3dbb270ff7f54b17916142b6701171e32023-11-19T21:22:47ZengMDPI AGCells2073-44092020-04-019494610.3390/cells9040946Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the DiseaseBarun Das0Kevin Okamoto1John Rabalais2Ronald R. Marchelletta3Kim E. Barrett4Soumita Das5Maho Niwa6Mamata Sivagnanam7Department of Pediatrics, University of California, San Diego, CA 92093, USADepartment of Pediatrics, University of California, San Diego, CA 92093, USADepartment of Pediatrics, University of California, San Diego, CA 92093, USADepartment of Medicine, University of California, San Diego, CA 92093, USADepartment of Medicine, University of California, San Diego, CA 92093, USADepartment of Pathology, University of California, San Diego, CA 92093, USADivision of Biological Sciences, University of California, San Diego, CA 92093, USADepartment of Pediatrics, University of California, San Diego, CA 92093, USACongenital 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 <i>XBP1</i> 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.https://www.mdpi.com/2073-4409/9/4/946congenital tufting enteropathymutant EpCAMER stressunfolded protein response |
| spellingShingle | Barun Das Kevin Okamoto John Rabalais Ronald R. Marchelletta Kim E. Barrett Soumita Das Maho Niwa Mamata Sivagnanam Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease Cells congenital tufting enteropathy mutant EpCAM ER stress unfolded protein response |
| title | Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease |
| title_full | Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease |
| title_fullStr | Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease |
| title_full_unstemmed | Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease |
| title_short | Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease |
| title_sort | congenital tufting enteropathy associated mutant of epithelial cell adhesion molecule activates the unfolded protein response in a murine model of the disease |
| topic | congenital tufting enteropathy mutant EpCAM ER stress unfolded protein response |
| url | https://www.mdpi.com/2073-4409/9/4/946 |
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