Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability

Detalhes bibliográficos
Autor(a) principal: Loureiro, Cláudia Almeida
Data de Publicação: 2019
Outros Autores: Santos, João D., Matos, Ana Margarida, Jordan, Peter, Matos, Paulo, Farinha, Carlos M., Pinto, Francisco R.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/6543
Resumo: Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31231217/
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spelling Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane StabilityChloride TransportCystic FibrosisCFTRProtein NetworkCell SignalingPlasma MembraneComputational BiologyVias de Transdução de Sinal e Patologias AssociadasFree PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31231217/In cystic fibrosis, the most common disease-causing mutation is F508del, which causes not only intracellular retention and degradation of CFTR, but also defective channel gating and decreased membrane stability of the small amount that reaches the plasma membrane (PM). Thus, pharmacological correction of mutant CFTR requires targeting of multiple cellular defects in order to achieve clinical benefit. Although small-molecule compounds have been identified and commercialized that can correct its folding or gating, an efficient retention of F508del CFTR at the PM has not yet been explored pharmacologically despite being recognized as a crucial factor for improving functional rescue of chloride transport. In ongoing efforts to determine the CFTR interactome at the PM, we used three complementary approaches: targeting proteins binding to tyrosine-phosphorylated CFTR, protein complexes involved in cAMP-mediated CFTR stabilization at the PM, and proteins selectively interacting at the PM with rescued F508del-CFTR but not wt-CFTR. Using co-immunoprecipitation or peptide-pull down strategies, we identified around 400 candidate proteins through sequencing of complex protein mixtures using the nano-LC Triple TOF MS technique. Key candidate proteins were validated for their robust interaction with CFTR-containing protein complexes and for their ability to modulate the amount of CFTR expressed at the cell surface of bronchial epithelial cells. Here, we describe how we explored the abovementioned experimental datasets to build a protein interaction network with the aim of identifying novel pharmacological targets to rescue CFTR function in cystic fibrosis (CF) patients. We identified and validated novel candidate proteins that were essential components of the network but not detected in previous proteomic analyses.This work was supported by FCT, Portugal, through center grant UID/MULTI/04046/2019 to BioISI and the BioSys PhD program PD65-2012 (fellowships SFRH/BD/52488/2014, SFRH/ BD/106084/2015, and SFRH/BD/52490/2014 to CL, JS, and AM, respectively).Frontiers MediaRepositório Científico do Instituto Nacional de SaúdeLoureiro, Cláudia AlmeidaSantos, João D.Matos, Ana MargaridaJordan, PeterMatos, PauloFarinha, Carlos M.Pinto, Francisco R.2020-04-28T20:49:13Z2019-06-042019-06-04T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/6543engFront Pharmacol. 2019 Jun 4;10:619. doi: 10.3389/fphar.2019.00619. eCollection 20191663-981210.3389/fphar.2019.00619info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:41:26Zoai:repositorio.insa.pt:10400.18/6543Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:41:07.074404Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
title Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
spellingShingle Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
Loureiro, Cláudia Almeida
Chloride Transport
Cystic Fibrosis
CFTR
Protein Network
Cell Signaling
Plasma Membrane
Computational Biology
Vias de Transdução de Sinal e Patologias Associadas
title_short Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
title_full Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
title_fullStr Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
title_full_unstemmed Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
title_sort Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability
author Loureiro, Cláudia Almeida
author_facet Loureiro, Cláudia Almeida
Santos, João D.
Matos, Ana Margarida
Jordan, Peter
Matos, Paulo
Farinha, Carlos M.
Pinto, Francisco R.
author_role author
author2 Santos, João D.
Matos, Ana Margarida
Jordan, Peter
Matos, Paulo
Farinha, Carlos M.
Pinto, Francisco R.
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Loureiro, Cláudia Almeida
Santos, João D.
Matos, Ana Margarida
Jordan, Peter
Matos, Paulo
Farinha, Carlos M.
Pinto, Francisco R.
dc.subject.por.fl_str_mv Chloride Transport
Cystic Fibrosis
CFTR
Protein Network
Cell Signaling
Plasma Membrane
Computational Biology
Vias de Transdução de Sinal e Patologias Associadas
topic Chloride Transport
Cystic Fibrosis
CFTR
Protein Network
Cell Signaling
Plasma Membrane
Computational Biology
Vias de Transdução de Sinal e Patologias Associadas
description Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31231217/
publishDate 2019
dc.date.none.fl_str_mv 2019-06-04
2019-06-04T00:00:00Z
2020-04-28T20:49:13Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.18/6543
url http://hdl.handle.net/10400.18/6543
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Front Pharmacol. 2019 Jun 4;10:619. doi: 10.3389/fphar.2019.00619. eCollection 2019
1663-9812
10.3389/fphar.2019.00619
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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