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Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum

1
BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande C8, 1749-016 Lisboa, Portugal
2
CEDOC-Chronic Diseases Research Centre, Nova Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Rua Câmara Pestana, 1150-082 Lisboa, Portugal
3
Proteomics Core Facility-SGIKER, University of the Basque Country UPV/EHU, Barrio Sariena, 48940 Vizcaya, Spain
4
LASIGE, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisbon, Portugal
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(4), 353; https://doi.org/10.3390/cells8040353
Received: 28 February 2019 / Revised: 9 April 2019 / Accepted: 12 April 2019 / Published: 14 April 2019
(This article belongs to the Special Issue Unconventional Protein Secretion in Development and Disease)
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Abstract

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. View Full-Text
Keywords: CFTR; endoplasmic reticulum quality control; arginine-framed tripeptides; diacidic code; interactome; folding; trafficking CFTR; endoplasmic reticulum quality control; arginine-framed tripeptides; diacidic code; interactome; folding; trafficking
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Santos, J.D.; Canato, S.; Carvalho, A.S.; Botelho, H.M.; Aloria, K.; Amaral, M.D.; Matthiesen, R.; Falcao, A.O.; Farinha, C.M. Folding Status Is Determinant over Traffic-Competence in Defining CFTR Interactors in the Endoplasmic Reticulum. Cells 2019, 8, 353.

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