Cargando…

Defective proteostasis in celiac disease as a new therapeutic target

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 t...

Descripción completa

Detalles Bibliográficos
Autores principales: Maiuri, Luigi, Villella, Valeria R, Piacentini, Mauro, Raia, Valeria, Kroemer, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368542/
https://www.ncbi.nlm.nih.gov/pubmed/30737369
http://dx.doi.org/10.1038/s41419-019-1392-9
_version_ 1783393997383794688
author Maiuri, Luigi
Villella, Valeria R
Piacentini, Mauro
Raia, Valeria
Kroemer, Guido
author_facet Maiuri, Luigi
Villella, Valeria R
Piacentini, Mauro
Raia, Valeria
Kroemer, Guido
author_sort Maiuri, Luigi
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6368542
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-63685422019-02-11 Defective proteostasis in celiac disease as a new therapeutic target Maiuri, Luigi Villella, Valeria R Piacentini, Mauro Raia, Valeria Kroemer, Guido Cell Death Dis Review Article 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. Nature Publishing Group UK 2019-02-08 /pmc/articles/PMC6368542/ /pubmed/30737369 http://dx.doi.org/10.1038/s41419-019-1392-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Review Article
Maiuri, Luigi
Villella, Valeria R
Piacentini, Mauro
Raia, Valeria
Kroemer, Guido
Defective proteostasis in celiac disease as a new therapeutic target
title Defective proteostasis in celiac disease as a new therapeutic target
title_full Defective proteostasis in celiac disease as a new therapeutic target
title_fullStr Defective proteostasis in celiac disease as a new therapeutic target
title_full_unstemmed Defective proteostasis in celiac disease as a new therapeutic target
title_short Defective proteostasis in celiac disease as a new therapeutic target
title_sort defective proteostasis in celiac disease as a new therapeutic target
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368542/
https://www.ncbi.nlm.nih.gov/pubmed/30737369
http://dx.doi.org/10.1038/s41419-019-1392-9
work_keys_str_mv AT maiuriluigi defectiveproteostasisinceliacdiseaseasanewtherapeutictarget
AT villellavaleriar defectiveproteostasisinceliacdiseaseasanewtherapeutictarget
AT piacentinimauro defectiveproteostasisinceliacdiseaseasanewtherapeutictarget
AT raiavaleria defectiveproteostasisinceliacdiseaseasanewtherapeutictarget
AT kroemerguido defectiveproteostasisinceliacdiseaseasanewtherapeutictarget