Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/1533
Título: BAG-1 stabilizes mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner
Autor: Mendes, Filipa
Farinha, Carlos M.
Felício, Verónica
Alves, Paula C.
Vieira, Isabel
Amaral, Paulo C.
Palavras-chave: Fibrose Quística
Doenças Genéticas
Data: Out-2012
Editora: Karger
Citação: Cell Physiol Biochem. 2012;30(5):1120-33. doi: 10.1159/000343303. Epub 2012 Oct 5
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.
Peer review: yes
URI: http://hdl.handle.net/10400.18/1533
ISSN: 1015-8987
Versão do Editor: http://www.karger.com/Article/Abstract/343303
Aparece nas colecções:DGH - Artigos em revistas internacionais

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