Publication
Rescue of F508del-CFTR by RXR motif inactivation triggers proteome modulation associated with the unfolded protein response
| dc.contributor.author | Gomes-Alves, Patrícia | |
| dc.contributor.author | Couto, Francisco | |
| dc.contributor.author | Pesquita, Cátia | |
| dc.contributor.author | Coelho, Ana V. | |
| dc.contributor.author | Penque, Deborah | |
| dc.date.accessioned | 2011-09-13T16:31:16Z | |
| dc.date.available | 2011-09-13T16:31:16Z | |
| dc.date.issued | 2010-04 | |
| dc.description.abstract | F508del-CFTR, the most common mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, disrupts intracellular trafficking leading to cystic fibrosis (CF). The trafficking defect of F508del-CFTR can be rescued by simultaneous inactivation of its four RXR motifs (4RK). Proteins involved in the F508del-CFTR trafficking defect and/or rescue are therefore potential CF therapeutic targets. We sought to identify these proteins by investigating differential proteome modulation in BHK cells over-expressing wt-CFTR, F508del-CFTR or the revertant F508del/4RK-CFTR. By 2-dimensional electrophoresis-based proteomics and western blot approaches we demonstrated that over-expression of F508del/4RK-CFTR modulates the expression of a large number of proteins, many of which are reported interactors of CFTR and/ or 14-3-3 with potential roles in CFTR trafficking. GRP78/BiP, a marker of ER stress and unfolded protein response (UPR), is up-regulated in cells over-expressing either F508del-CFTR or F598del/4RK-CFTR. However, over-expression of F508del/4RK-CFTR induces the up-regulation of many other UPR-associated proteins (e.g. GRP94, PDI, GRP75/mortalin) and, interestingly, the down-regulation of proteasome components associated with CFTR degradation, such as the proteasome activator PA28 (PSME2) and COP9 signalosome (COPS5/CSN5). Moreover, the F508del-CFTR-induced proteostasis imbalance, which involves some heat shock chaperones (e.g. HSP72/Hpa2), ER-EF-hand Ca2+-binding proteins (calumenin) and the proteasome activator PA28 (PSME2), tends to be ‘restored’, i.e., in BHK cells over-expressing F508del/4RK-CFTR those proteins tend to have expression levels similar to the wild-type ones. These findings indicate that a particular cellular environment orchestrated by the UPR contributes to and/or is compatible with F508del/4RK-CFTR rescue. | por |
| dc.identifier.citation | Biochim Biophys Acta. 2010 Apr;1804(4):856-65. Epub 2010 Jan 4 | por |
| dc.identifier.issn | 1570-9639 | |
| dc.identifier.other | doi:10.1016/j.bbapap.2009.12.013 | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/155 | |
| dc.language.iso | eng | por |
| dc.peerreviewed | yes | por |
| dc.publisher | Elsevier | por |
| dc.relation.publisherversion | http://www.sciencedirect.com/science/article/pii/S1570963909003823 | por |
| dc.subject | Cystic fibrosis | por |
| dc.subject | CFTR | por |
| dc.subject | Unfolded protein response | por |
| dc.subject | Protein trafficking | por |
| dc.subject | RXR motif | por |
| dc.subject | Therapeutic target | por |
| dc.subject | Genómica Funcional e Estrutural | por |
| dc.title | Rescue of F508del-CFTR by RXR motif inactivation triggers proteome modulation associated with the unfolded protein response | por |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.citation.endPage | 865 | por |
| oaire.citation.startPage | 856 | por |
| oaire.citation.title | Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics | por |
| rcaap.rights | restrictedAccess | por |
| rcaap.type | article | por |