Cystic fibrosis transmembrane conductance regulator (CFTR) and autophagy: hereditary defects in cystic fibrosis <i>versus</i> gluten-mediated inhibition in celiac disease

// Luigi Maiuri 1 , 2 , Valeria Raia 3 , Mauro Piacentini 4 , 5 , Antonella Tosco 3 , Valeria Rachela Villella 2 and Guido Kroemer 6 , 7 , 8 , 9 , 10 , 11 , 12 1 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy 2 European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy 3 Department of Translational Medical Sciences, Pediatric Unit, Regional Cystic Fibrosis Center, Federico II University Naples, Naples, Italy 4 Department of Biology, University of Rome "Tor Vergata", Rome, Italy 5 National Institute for Infectious Diseases, IRCCS 'L. Spallanzani', Rome, Italy 6 Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France 7 INSERM U1138, Centre de Recherche des Cordeliers, Paris, France 8 Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France 9 Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France 10 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France 11 Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden 12 Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China Correspondence to: Guido Kroemer, email: kroemer@orange.fr Valeria Rachela Villella, email: valeria.villella@gmail.com Keywords: CFTR; cystic fibrosis; autophagy; celiac disease; transglutaminase 2 Received: March 03, 2019 Accepted: June 05, 2019 Published: July 09, 2019 ABSTRACT Cystic Fibrosis (CF) is the most frequent lethal monogenetic disease affecting humans. CF is characterized by mutations in cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel whose malfunction triggers the activation of transglutaminase-2 (TGM2), as well as the inactivation of the Beclin-1 (BECN1) complex resulting in disabled autophagy. CFTR inhibition, TGM2 activation and BECN1 sequestration engage in an 'infernal trio' that locks the cell in a pro-inflammatory state through anti-homeostatic feedforward loops. Thus, stimulation of CFTR function, TGM2 inhibition and autophagy stimulation can be used to treat CF patients. Several studies indicate that patients with CF have a higher incidence of celiac disease (CD) and that mice bearing genetically determined CFTR defects are particularly sensitive to the enteropathogenic effects of the orally supplied gliadin (a gluten-derived protein). A gluten/gliadin-derived peptide (P31–43) inhibits CFTR in mouse intestinal epithelial cells, causing a local stress response that contributes to the immunopathology of CD. In particular, P31–43-induced CFTR inhibition elicits an epithelial stress response perturbing proteostasis. This event triggers TGM2 activation, BECN1 sequestration and results in molecular crosslinking of CFTR and P31-43 by TGM2. Importantly, stimulation of CFTR function with a pharmacological potentiator (Ivacaftor), which is approved for the treatment of CF, could attenuate the autophagy-inhibition and pro-inflammatory effects of gliadin in preclinical models of CD. Thus, CD shares with CF a common molecular mechanism involving CFTR inhibition that might respond to drugs that intercept the "infernal trio". Here, we highlight how drugs available for CF treatment could be repurposed for the therapy of CD.