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Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum
The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the ER is mediated by sp...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523853/ https://www.ncbi.nlm.nih.gov/pubmed/31014000 http://dx.doi.org/10.3390/cells8040353 |
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author | Santos, João D. Canato, Sara Carvalho, Ana S. Botelho, Hugo M. Aloria, Kerman Amaral, Margarida D. Matthiesen, Rune Falcao, Andre O. Farinha, Carlos M. |
author_facet | Santos, João D. Canato, Sara Carvalho, Ana S. Botelho, Hugo M. Aloria, Kerman Amaral, Margarida D. Matthiesen, Rune Falcao, Andre O. Farinha, Carlos M. |
author_sort | Santos, João D. |
collection | PubMed |
description | The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the ER is mediated by specific retention/sorting signals that include four arginine-framed tripeptide (AFT) retention motifs and a diacidic (DAD) exit code that controls the interaction with the COPII machinery. Here, we aim at obtaining a global view of the protein interactors that regulate CFTR exit from the ER. We used mass spectrometry-based interaction proteomics and bioinformatics analyses to identify and characterize proteins interacting with selected CFTR peptide motifs or full-length CFTR variants retained or bypassing these ERQC checkpoints. We conclude that these ERQC trafficking checkpoints rely on fundamental players in the secretory pathway, detecting key components of the protein folding machinery associated with the AFT recognition and of the trafficking machinery recognizing the diacidic code. Furthermore, a greater similarity in terms of interacting proteins is observed for variants sharing the same folding defect over those reaching the same cellular location, evidencing that folding status is dominant over ER escape in shaping the CFTR interactome. |
format | Online Article Text |
id | pubmed-6523853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65238532019-06-03 Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum Santos, João D. Canato, Sara Carvalho, Ana S. Botelho, Hugo M. Aloria, Kerman Amaral, Margarida D. Matthiesen, Rune Falcao, Andre O. Farinha, Carlos M. Cells Article The most common cystic fibrosis-causing mutation (F508del, present in ~85% of CF patients) leads to CFTR misfolding, which is recognized by the endoplasmic reticulum (ER) quality control (ERQC), resulting in ER retention and early degradation. It is known that CFTR exit from the ER is mediated by specific retention/sorting signals that include four arginine-framed tripeptide (AFT) retention motifs and a diacidic (DAD) exit code that controls the interaction with the COPII machinery. Here, we aim at obtaining a global view of the protein interactors that regulate CFTR exit from the ER. We used mass spectrometry-based interaction proteomics and bioinformatics analyses to identify and characterize proteins interacting with selected CFTR peptide motifs or full-length CFTR variants retained or bypassing these ERQC checkpoints. We conclude that these ERQC trafficking checkpoints rely on fundamental players in the secretory pathway, detecting key components of the protein folding machinery associated with the AFT recognition and of the trafficking machinery recognizing the diacidic code. Furthermore, a greater similarity in terms of interacting proteins is observed for variants sharing the same folding defect over those reaching the same cellular location, evidencing that folding status is dominant over ER escape in shaping the CFTR interactome. MDPI 2019-04-14 /pmc/articles/PMC6523853/ /pubmed/31014000 http://dx.doi.org/10.3390/cells8040353 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Santos, João D. Canato, Sara Carvalho, Ana S. Botelho, Hugo M. Aloria, Kerman Amaral, Margarida D. Matthiesen, Rune Falcao, Andre O. Farinha, Carlos M. Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum |
title | Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum |
title_full | Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum |
title_fullStr | Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum |
title_full_unstemmed | Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum |
title_short | Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum |
title_sort | folding status is determinant over traffic-competence in defining cftr interactors in the endoplasmic reticulum |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523853/ https://www.ncbi.nlm.nih.gov/pubmed/31014000 http://dx.doi.org/10.3390/cells8040353 |
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