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Network Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stability

2019-06-04Journal article Open access
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dc.contributor.authorLoureiro, Cláudia Almeida
dc.contributor.authorSantos, João D.
dc.contributor.authorMatos, Ana Margarida
dc.contributor.authorJordan, Peter
dc.contributor.authorMatos, Paulo
dc.contributor.authorFarinha, Carlos M.
dc.contributor.authorPinto, Francisco R.
dc.date.accessioned2020-04-28T20:49:13Z
dc.date.available2020-04-28T20:49:13Z
dc.date.issued2019-06-04
dc.descriptionFree PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31231217/pt_PT
dc.description.abstractIn 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.pt_PT
dc.description.sponsorshipThis 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).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Pharmacol. 2019 Jun 4;10:619. doi: 10.3389/fphar.2019.00619. eCollection 2019pt_PT
dc.identifier.doi10.3389/fphar.2019.00619pt_PT
dc.identifier.issn1663-9812
dc.identifier.urihttp://hdl.handle.net/10400.18/6543
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontiers Mediapt_PT
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fphar.2019.00619/fullpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectChloride Transportpt_PT
dc.subjectCystic Fibrosispt_PT
dc.subjectCFTRpt_PT
dc.subjectProtein Networkpt_PT
dc.subjectCell Signalingpt_PT
dc.subjectPlasma Membranept_PT
dc.subjectComputational Biologypt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleNetwork Biology Identifies Novel Regulators of CFTR Trafficking and Membrane Stabilitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04046%2F2013/PT
oaire.citation.startPage619pt_PT
oaire.citation.titleFrontiers in Pharmacologypt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream5876
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctDe acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationdc84f768-e6f2-4eea-b294-6c8ebbd1a156
relation.isProjectOfPublication.latestForDiscoverydc84f768-e6f2-4eea-b294-6c8ebbd1a156

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