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...
Autores principales: | , , , , |
---|---|
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 |