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Cell Death Dis. 2019 Feb 8;10(2):114. doi: 10.1038/s41419-019-1392-9.

Defective proteostasis in celiac disease as a new therapeutic target.

Maiuri L1,2, Villella VR3, Piacentini M4,5, Raia V6, Kroemer G7,8,9,10,11,12.

Author information

1
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy. luigi.maiuri@gmail.com.
2
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy. luigi.maiuri@gmail.com.
3
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy.
4
Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
5
National Institute for Infectious Diseases IRCCS 'L. Spallanzani', Rome, Italy.
6
Department of Translational Medical Sciences, Pediatric Unit, Regional Cystic Fibrosis Center, Federico II University Naples, Naples, Italy.
7
Equipe11 labellisée Ligue Nationale contrele Cancer, Centre de Recherche des Cordeliers, Paris, France. kroemer@orange.fr.
8
INSERM U1138, Centre de Recherche des Cordeliers, Paris, France. kroemer@orange.fr.
9
Université Paris Descartes, Paris, France. kroemer@orange.fr.
10
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. kroemer@orange.fr.
11
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. kroemer@orange.fr.
12
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, 17176, Sweden. kroemer@orange.fr.

Abstract

Cystic fibrosis (CF) is a disease caused by loss-of-function mutations affecting the CF transmembrane conductance regulator (CFTR), a chloride channel. Recent evidence indicates that CFTR is inhibited by a gluten/gliadin-derived peptide (P31-43), causing an acquired state of CFTR inhibition within the gut that contributes to the pathogenesis of celiac disease (CD). Of note, CFTR inhibition does not only cause intra- and extracellular ion imbalances but also affects proteostasis by activating transglutaminase-2 (TGM2) and by disabling autophagy. These three phenomena (CFTR inhibition, TGM2 activation, and autophagy impairment) engage in multiple self-amplifying circuitries, thus forming an "infernal trio". The trio hinders enterocytes from returning to homeostasis and instead locks them in an irreversible pro-inflammatory state that ultimately facilitates T lymphocyte-mediated immune responses against another gluten/gliadin-derived peptide (P57-68), which,upon deamidation by activated TGM2, becomes fully antigenic. Hence, the pathogenic protein gliadin exemplifies a food constituent the exceptional immunogenicity of which arises from a combination of antigenicity (conferred by deaminated P57-68) and adjuvanticity (conferred by P31-43). CF can be treated by agents targeting the "infernal trio" including CFTR potentiators, TGM2 inhibitors, and autophagy enhancers. We speculate that such agents may also be used for CD therapy and indeed could constitute close-to-etiological treatments of this enteropathy.

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