Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1 alpha/JNK Pathway in an Intestinal Epithelial Cell Model
Por:
Maeyashiki C, Melhem H, Hering L, Baebler K, Cosin-Roger J, Schefer F, Weder B, Hausmann M, Scharl M, Rogler G, de Vallière C and Ruiz PA
Publicada:
29 ene 2020
Ahead of Print:
29 ene 2020
Categoría:
Multidisciplinary
Resumen:
Proton-sensing ovarian cancer G-protein coupled receptor (OGR1) plays an important role in pH homeostasis. Acidosis occurs at sites of intestinal inflammation and can induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), an evolutionary mechanism that enables cells to cope with stressful conditions. ER stress activates autophagy, and both play important roles in gut homeostasis and contribute to the pathogenesis of inflammatory bowel disease (IBD). Using a human intestinal epithelial cell model, we investigated whether our previously observed protective effects of OGR1 deficiency in experimental colitis are associated with a differential regulation of ER stress, the UPR and autophagy. Caco-2 cells stably overexpressing OGR1 were subjected to an acidic pH shift. pH-dependent OGR1-mediated signalling led to a significant upregulation in the ER stress markers, binding immunoglobulin protein (BiP) and phospho-inositol required 1 alpha (IRE1 alpha), which was reversed by a novel OGR1 inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor. Proton-activated OGR1-mediated signalling failed to induce apoptosis, but triggered accumulation of total microtubule-associated protein 1A/1B-light chain 3, suggesting blockage of late stage autophagy. Our results show novel functions for OGR1 in the regulation of ER stress through the IRE1 alpha -JNK signalling pathway, as well as blockage of autophagosomal degradation. OGR1 inhibition might represent a novel therapeutic approach in IBD.
Filiaciones:
Maeyashiki C:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Melhem H:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Hering L:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Baebler K:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Schefer F:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Weder B:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Hausmann M:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Scharl M:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Zurich Center for Integrative Human Physiology, Zurich, Switzerland
Rogler G:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Zurich Center for Integrative Human Physiology, Zurich, Switzerland
de Vallière C:
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
gold, Green Published
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