BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner
Autor(a) principal: | |
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Data de Publicação: | 2012 |
Outros Autores: | , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/1533 |
Resumo: | Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the dysfunctional Cl- channel in Cystic Fibrosis, undergoes complex biosynthesis at the endoplasmic reticulum involving several molecular chaperones including Hsp70 and many co-chaperones. Bcl-2-associated athanogenes (BAGs) constitute a protein family sharing an Hsc70-binding domain. BAG-1 possesses an ubiquitin-like domain (Ub-LD) responsible for proteasomal association and for promoting substrate release from Hsc70/Hsp70 in vitro by accelerating the chaperone ATP/ADP exchange rate. Methods: Herein, we studied the in vivo effect of BAG-1 on the turnover and processing of wild type (wt)- and F508del-CFTR, the most frequent mutation in CF patients. Results: Results show that BAG-1 associates with both wt- and F508del-CFTR (in higher yields with the latter) through its Ub-LD and independently of Hsc70. Moreover, the immature form of F508del-CFTR (but not of wt-CFTR) is stabilized by BAG-1 overexpression, albeit in a cell-type specific way, without detectable maturation. Data also show that BAG-1 and the proteasome inhibitor ALLN are not additive on stabilizing F508del-CFTR and this effect depends on BAG-1 Ub-LD. Moreover, under BAG-1 overexpression, a reduction in ubiquitinylated-CFTR occurs suggesting that BAG-1 competes with Ub. Conclusion: Overall, data are compatible with a mechanism in which BAG-1 stabilizes F508del-CFTR by direct binding, probably competing out ubiquitin to partially avoid its proteasomal degradation. |
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7160 |
spelling |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent MannerFibrose QuísticaCFTRERADBAG-1Hsp70UbiquitinaDoenças GenéticasCystic Fibrosis Transmembrane Conductance Regulator (CFTR), the dysfunctional Cl- channel in Cystic Fibrosis, undergoes complex biosynthesis at the endoplasmic reticulum involving several molecular chaperones including Hsp70 and many co-chaperones. Bcl-2-associated athanogenes (BAGs) constitute a protein family sharing an Hsc70-binding domain. BAG-1 possesses an ubiquitin-like domain (Ub-LD) responsible for proteasomal association and for promoting substrate release from Hsc70/Hsp70 in vitro by accelerating the chaperone ATP/ADP exchange rate. Methods: Herein, we studied the in vivo effect of BAG-1 on the turnover and processing of wild type (wt)- and F508del-CFTR, the most frequent mutation in CF patients. Results: Results show that BAG-1 associates with both wt- and F508del-CFTR (in higher yields with the latter) through its Ub-LD and independently of Hsc70. Moreover, the immature form of F508del-CFTR (but not of wt-CFTR) is stabilized by BAG-1 overexpression, albeit in a cell-type specific way, without detectable maturation. Data also show that BAG-1 and the proteasome inhibitor ALLN are not additive on stabilizing F508del-CFTR and this effect depends on BAG-1 Ub-LD. Moreover, under BAG-1 overexpression, a reduction in ubiquitinylated-CFTR occurs suggesting that BAG-1 competes with Ub. Conclusion: Overall, data are compatible with a mechanism in which BAG-1 stabilizes F508del-CFTR by direct binding, probably competing out ubiquitin to partially avoid its proteasomal degradation.KargerRepositório Científico do Instituto Nacional de SaúdeMendes, FilipaFarinha, Carlos M.Felício, VerónicaAlves, Paula C.Vieira, IsabelAmaral, Paulo C.2013-03-22T11:59:09Z2012-102012-10-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/1533engCell Physiol Biochem. 2012;30(5):1120-33. doi: 10.1159/000343303. Epub 2012 Oct 51015-8987doi: 10.1159/000343303info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:38:47Zoai:repositorio.insa.pt:10400.18/1533Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:36:38.103181Repositório 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 |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
title |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
spellingShingle |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner Mendes, Filipa Fibrose Quística CFTR ERAD BAG-1 Hsp70 Ubiquitina Doenças Genéticas |
title_short |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
title_full |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
title_fullStr |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
title_full_unstemmed |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
title_sort |
BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner |
author |
Mendes, Filipa |
author_facet |
Mendes, Filipa Farinha, Carlos M. Felício, Verónica Alves, Paula C. Vieira, Isabel Amaral, Paulo C. |
author_role |
author |
author2 |
Farinha, Carlos M. Felício, Verónica Alves, Paula C. Vieira, Isabel Amaral, Paulo C. |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Mendes, Filipa Farinha, Carlos M. Felício, Verónica Alves, Paula C. Vieira, Isabel Amaral, Paulo C. |
dc.subject.por.fl_str_mv |
Fibrose Quística CFTR ERAD BAG-1 Hsp70 Ubiquitina Doenças Genéticas |
topic |
Fibrose Quística CFTR ERAD BAG-1 Hsp70 Ubiquitina Doenças Genéticas |
description |
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the dysfunctional Cl- channel in Cystic Fibrosis, undergoes complex biosynthesis at the endoplasmic reticulum involving several molecular chaperones including Hsp70 and many co-chaperones. Bcl-2-associated athanogenes (BAGs) constitute a protein family sharing an Hsc70-binding domain. BAG-1 possesses an ubiquitin-like domain (Ub-LD) responsible for proteasomal association and for promoting substrate release from Hsc70/Hsp70 in vitro by accelerating the chaperone ATP/ADP exchange rate. Methods: Herein, we studied the in vivo effect of BAG-1 on the turnover and processing of wild type (wt)- and F508del-CFTR, the most frequent mutation in CF patients. Results: Results show that BAG-1 associates with both wt- and F508del-CFTR (in higher yields with the latter) through its Ub-LD and independently of Hsc70. Moreover, the immature form of F508del-CFTR (but not of wt-CFTR) is stabilized by BAG-1 overexpression, albeit in a cell-type specific way, without detectable maturation. Data also show that BAG-1 and the proteasome inhibitor ALLN are not additive on stabilizing F508del-CFTR and this effect depends on BAG-1 Ub-LD. Moreover, under BAG-1 overexpression, a reduction in ubiquitinylated-CFTR occurs suggesting that BAG-1 competes with Ub. Conclusion: Overall, data are compatible with a mechanism in which BAG-1 stabilizes F508del-CFTR by direct binding, probably competing out ubiquitin to partially avoid its proteasomal degradation. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-10 2012-10-01T00:00:00Z 2013-03-22T11:59:09Z |
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/10400.18/1533 |
url |
http://hdl.handle.net/10400.18/1533 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Cell Physiol Biochem. 2012;30(5):1120-33. doi: 10.1159/000343303. Epub 2012 Oct 5 1015-8987 doi: 10.1159/000343303 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Karger |
publisher.none.fl_str_mv |
Karger |
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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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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 |
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