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

Autor: Kerman Aloria, Margarida D. Amaral, Carlos M. Farinha, João D. Santos, André O. Falcão, Ana Sofia Carvalho, Rune Matthiesen, Sara Canato, Hugo M. Botelho
Přispěvatelé: Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Cells
Volume 8
Issue 4
Addi. Archivo Digital para la Docencia y la Investigación
instname
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
Cells, Vol 8, Iss 4, p 353 (2019)
ISSN: 2073-4409
DOI: 10.3390/cells8040353
Popis: 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. Award to C.M.F., S.C., J.D.S., and H.M.B. are recipients of fellowships from the BioSys PhD program PD/BD/114393/2016 (SFRH/BD/52491/2014), PD/BD/106084/2015 (SFRH/BD/106084/2015) and SFRH/BPD/93017/2013 from FCT, Portugal, respectively. Proteomics Core Facility-SGIKER is part of the ProteoRed-ISCIII network and is partially funded by ERDF and ESF.
Databáze: OpenAIRE
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