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Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease.
Das, Barun; Okamoto, Kevin; Rabalais, John; Marchelletta, Ronald R; Barrett, Kim E; Das, Soumita; Niwa, Maho; Sivagnanam, Mamata.
Afiliación
  • Das B; Department of Pediatrics, University of California, San Diego, CA 92093, USA.
  • Okamoto K; Department of Pediatrics, University of California, San Diego, CA 92093, USA.
  • Rabalais J; Department of Pediatrics, University of California, San Diego, CA 92093, USA.
  • Marchelletta RR; Department of Medicine, University of California, San Diego, CA 92093, USA.
  • Barrett KE; Department of Medicine, University of California, San Diego, CA 92093, USA.
  • Das S; Department of Pathology, University of California, San Diego, CA 92093, USA.
  • Niwa M; Division of Biological Sciences, University of California, San Diego, CA 92093, USA.
  • Sivagnanam M; Department of Pediatrics, University of California, San Diego, CA 92093, USA.
Cells ; 9(4)2020 04 11.
Article en En | MEDLINE | ID: mdl-32290509
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diarrea Infantil / Respuesta de Proteína Desplegada / Molécula de Adhesión Celular Epitelial / Síndromes de Malabsorción Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans / Newborn Idioma: En Revista: Cells Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diarrea Infantil / Respuesta de Proteína Desplegada / Molécula de Adhesión Celular Epitelial / Síndromes de Malabsorción Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans / Newborn Idioma: En Revista: Cells Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza