A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease
| العنوان: | A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease |
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| المؤلفون: | Mara C. Spinella, Romina Monzani, Luigi Maiuri, Alessandro Luciani, Federica Rossin, Mauro Piacentini, Giorgia Renga, Christian Grimm, Guido Kroemer, Marco Silano, Valeria Raia, Enrico Garaci, Stefano Guido, Vasilis Oikonomou, Antonella Tosco, Valeria Rachela Villella, Andrea Venerando, Giorgio Cozza, Eleonora Ferrari, Speranza Esposito, Yu-Kai Chao, Luigina Romani |
| المساهمون: | Villella, Vr, Venerando, A, Cozza, G, Esposito, S, Ferrari, E, Monzani, R, Spinella, Mc, Oikonomou, V, Renga, G, Tosco, A, Rossin, F, Guido, S, Silano, Angelo, Garaci, E, Chao, Yk, Grimm, C, Luciani, A, Romani, L, Piacentini, M, Raia, V, Kroemer, G, Maiuri, L |
| المصدر: | The EMBO Journal |
| بيانات النشر: | EMBO, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, Genetics and Molecular Biology (all), Protein Conformation, Immunology and Microbiology (all), Tissue transglutaminase, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, Biochemistry, Mice, 0302 clinical medicine, News & Views, Molecular Biology of Disease, Membrane & Intracellular Transport, CFTR, Child, 0303 health sciences, P31–43 peptide, celiac disease, gliadin, mucosal immunology, biology, General Neuroscience, Inflammasome, Articles, Cystic fibrosis transmembrane conductance regulator, Cell biology, Neuroscience (all), Molecular Biology, Female, Protein Binding, medicine.drug, Settore BIO/06, Adolescent, Glutens, Immunology, Down-Regulation, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Young Adult, 03 medical and health sciences, Immune system, Protein Domains, medicine, Animals, Humans, 030304 developmental biology, Innate immune system, General Immunology and Microbiology, nutritional and metabolic diseases, Biochemistry, Genetics and Molecular Biology (all), Potentiator, Peptide Fragments, digestive system diseases, Disease Models, Animal, Mucosal immunology, biology.protein, Caco-2 Cells, Gliadin, 030217 neurology & neurosurgery |
| الوصف: | Intestinal handling of dietary proteins usually prevents local inflammatory and immune responses and promotes oral tolerance. However, in ~ 1% of the world population, gluten proteins from wheat and related cereals trigger an HLA DQ2/8‐restricted TH1 immune and antibody response leading to celiac disease. Prior epithelial stress and innate immune activation are essential for breaking oral tolerance to the gluten component gliadin. How gliadin subverts host intestinal mucosal defenses remains elusive. Here, we show that the α‐gliadin‐derived LGQQQPFPPQQPY peptide (P31–43) inhibits the function of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel pivotal for epithelial adaptation to cell‐autonomous or environmental stress. P31–43 binds to, and reduces ATPase activity of, the nucleotide‐binding domain‐1 (NBD1) of CFTR, thus impairing CFTR function. This generates epithelial stress, tissue transglutaminase and inflammasome activation, NF‐κB nuclear translocation and IL‐15 production, that all can be prevented by potentiators of CFTR channel gating. The CFTR potentiator VX‐770 attenuates gliadin‐induced inflammation and promotes a tolerogenic response in gluten‐sensitive mice and cells from celiac patients. Our results unveil a primordial role for CFTR as a central hub orchestrating gliadin activities and identify a novel therapeutic option for celiac disease. |
| تدمد: | 1460-2075 0261-4189 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a695adcb4f89e8bc0147757dfcdf119aTest https://doi.org/10.15252/embj.2018100101Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a695adcb4f89e8bc0147757dfcdf119a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602075 02614189 |
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