Defective proteostasis in celiac disease as a new therapeutic target

Luigi Maiuri, Valeria R. Villella, Mauro Piacentini, Valeria Raia, Guido Kroemer

Research output: Contribution to journalReview article

3 Citations (Scopus)

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.

Original languageEnglish
Article number114
Pages (from-to)1-7
Number of pages7
JournalCell Death and Disease
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

Fingerprint

Celiac Disease
Gliadin
Autophagy
Glutens
Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
Peptides
Chloride Channels
Enterocytes
Therapeutics
Homeostasis
Ions
T-Lymphocytes
Food
Mutation
transglutaminase 2
Proteins

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Defective proteostasis in celiac disease as a new therapeutic target. / Maiuri, Luigi; Villella, Valeria R.; Piacentini, Mauro; Raia, Valeria; Kroemer, Guido.

In: Cell Death and Disease, Vol. 10, No. 2, 114, 01.02.2019, p. 1-7.

Research output: Contribution to journalReview article

Maiuri, Luigi ; Villella, Valeria R. ; Piacentini, Mauro ; Raia, Valeria ; Kroemer, Guido. / Defective proteostasis in celiac disease as a new therapeutic target. In: Cell Death and Disease. 2019 ; Vol. 10, No. 2. pp. 1-7.
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