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

EMBO J. 2019 Jan 15;38(2):e100101. doi: 10.15252/embj.2018100101. Epub 2018 Nov 29.


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.

Keywords: CFTR; P31–43 peptide; celiac disease; gliadin; mucosal immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aminophenols / administration & dosage
  • Aminophenols / pharmacology
  • Animals
  • Caco-2 Cells
  • Celiac Disease / drug therapy
  • Celiac Disease / genetics
  • Celiac Disease / metabolism*
  • Cell Line
  • Child
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gliadin / pharmacology*
  • Humans
  • Male
  • Mice
  • Peptide Fragments / pharmacology*
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Domains
  • Quinolones / administration & dosage
  • Quinolones / pharmacology
  • Young Adult


  • Aminophenols
  • CFTR protein, human
  • Peptide Fragments
  • Quinolones
  • gliadin peptide (31-43)
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • Gliadin