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KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR
Cystic fibrosis (CF) is caused by mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), an anion-selective plasma membrane channel that mainly regulates chloride transport in a variety of epithelia. More than 2000 mutations, most of which presumed to be di...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455907/ https://www.ncbi.nlm.nih.gov/pubmed/36077010 http://dx.doi.org/10.3390/ijms23179612 |
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author | D’Amore, Claudio Borgo, Christian Bosello Travain, Valentina Salvi, Mauro |
author_facet | D’Amore, Claudio Borgo, Christian Bosello Travain, Valentina Salvi, Mauro |
author_sort | D’Amore, Claudio |
collection | PubMed |
description | Cystic fibrosis (CF) is caused by mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), an anion-selective plasma membrane channel that mainly regulates chloride transport in a variety of epithelia. More than 2000 mutations, most of which presumed to be disease-relevant, have been identified in the CFTR gene. The single CFTR mutation F508del (deletion of phenylalanine in position 508) is present in about 90% of global CF patients in at least one allele. F508del is responsible for the defective folding and processing of CFTR, failing to traffic to the plasma membrane and undergoing premature degradation via the ubiquitin–proteasome system. CFTR is subjected to different post-translational modifications (PTMs), and the possibility to modulate these PTMs has been suggested as a potential therapeutic strategy for the functional recovery of the disease-associated mutants. Recently, the PTM mapping of CFTR has identified some lysine residues that may undergo methylation or ubiquitination, suggesting a competition between these two PTMs. Our work hypothesis moves from the idea that favors methylation over ubiquitination, e.g., inhibiting demethylation could be a successful strategy for preventing the premature degradation of unstable CFTR mutants. Here, by using a siRNA library against all the human demethylases, we identified the enzymes whose downregulation increases F508del-CFTR stability and channel function. Our results show that KDM2A and KDM3B downregulation increases the stability of F508del-CFTR and boosts the functional rescue of the channel induced by CFTR correctors. |
format | Online Article Text |
id | pubmed-9455907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94559072022-09-09 KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR D’Amore, Claudio Borgo, Christian Bosello Travain, Valentina Salvi, Mauro Int J Mol Sci Article Cystic fibrosis (CF) is caused by mutations in the gene encoding of the cystic fibrosis transmembrane conductance regulator (CFTR), an anion-selective plasma membrane channel that mainly regulates chloride transport in a variety of epithelia. More than 2000 mutations, most of which presumed to be disease-relevant, have been identified in the CFTR gene. The single CFTR mutation F508del (deletion of phenylalanine in position 508) is present in about 90% of global CF patients in at least one allele. F508del is responsible for the defective folding and processing of CFTR, failing to traffic to the plasma membrane and undergoing premature degradation via the ubiquitin–proteasome system. CFTR is subjected to different post-translational modifications (PTMs), and the possibility to modulate these PTMs has been suggested as a potential therapeutic strategy for the functional recovery of the disease-associated mutants. Recently, the PTM mapping of CFTR has identified some lysine residues that may undergo methylation or ubiquitination, suggesting a competition between these two PTMs. Our work hypothesis moves from the idea that favors methylation over ubiquitination, e.g., inhibiting demethylation could be a successful strategy for preventing the premature degradation of unstable CFTR mutants. Here, by using a siRNA library against all the human demethylases, we identified the enzymes whose downregulation increases F508del-CFTR stability and channel function. Our results show that KDM2A and KDM3B downregulation increases the stability of F508del-CFTR and boosts the functional rescue of the channel induced by CFTR correctors. MDPI 2022-08-25 /pmc/articles/PMC9455907/ /pubmed/36077010 http://dx.doi.org/10.3390/ijms23179612 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article D’Amore, Claudio Borgo, Christian Bosello Travain, Valentina Salvi, Mauro KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR |
title | KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR |
title_full | KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR |
title_fullStr | KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR |
title_full_unstemmed | KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR |
title_short | KDM2A and KDM3B as Potential Targets for the Rescue of F508del-CFTR |
title_sort | kdm2a and kdm3b as potential targets for the rescue of f508del-cftr |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455907/ https://www.ncbi.nlm.nih.gov/pubmed/36077010 http://dx.doi.org/10.3390/ijms23179612 |
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