A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease

• Valeria R Villella ^[4] ; Andrea Venerando ^[5] ; Giorgio Cozza ^[6] ; Speranza Esposito ^[4] ; Eleonora Ferrari ^[7] ; Romina Monzani ^[7] ; Mara C Spinella ^[7] ; Vasilis Oikonomou ^[1] ; Giorgia Renga ^[1] ; Antonella Tosco ^[8] ; Federica Rossin ^[9] ; Stefano Guido ^[10] ; Marco Silano ^[11] ; Enrico Garaci ^[12] ; Yu‐Kai Chao ^[13] ; Christian Grimm ^[13] ; Alessandro Luciani ^[2] ; Luigina Romani ^[14] ; Mauro Piacentini ^[15] ; Valeria Raia ^[8] ; Guido Kroemer ^[3] ; Luigi Maiuri ^[7]
  1. [1] Università di Perugia

     Università di Perugia

     Perusa, Italia

     
  2. [2] University of Zurich

     University of Zurich

     Zürich, Suiza

     
  3. [3] Centre de Recherche des Cordeliers

     Centre de Recherche des Cordeliers

     París, Francia

     
  4. [4] 1 European Institute for Research in Cystic Fibrosis San Raffaele Scientific Institute Milan Italy
  5. [5] 2 Department of Comparative Biomedicine and Food Science University of Padova Padova Italy
  6. [6] 3 Department of Molecular Medicine University of Padova Padova Italy
  7. [7] 1 European Institute for Research in Cystic Fibrosis San Raffaele Scientific Institute Milan Italy; 4 Department of Health Sciences University of Eastern Piedmont Novara Italy
  8. [8] 6 Pediatric Unit Department of Translational Medical Sciences Regional Cystic Fibrosis Center Federico II University Naples Naples Italy
  9. [9] 7 Department of Biology University of Rome “Tor Vergata” Rome Italy
  10. [10] 8 Department of Chemical, Materials and Production Engineering Federico II University Naples Naples Italy
  11. [11] 9 Department of Food Safety, Nutrition and Veterinary Public Health Istituto Superiore di Sanità Roma Italy
  12. [12] 10 University San Raffaele and 21 IRCCS San Raffaele Rome Italy
  13. [13] 11 Department of Pharmacology and Toxicology Faculty of Medicine University of Munich (LMU) Munich Germany
  14. [14] 4 Department of Health Sciences University of Eastern Piedmont Novara Italy
  15. [15] 7 Department of Biology University of Rome “Tor Vergata” Rome Italy; 13 National Institute for Infectious Diseases IRCCS “L. Spallanzani” Rome Italy

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 2, 2019, pág. 2
• Idioma: inglés
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  • 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.