Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway.
Cell
; 146(5): 746-60, 2011 Sep 02.
Article
em En
| MEDLINE
| ID: mdl-21884936
ABSTRACT
The most prevalent disease-causing mutation of CFTR is the deletion of Phe508 (ΔF508), which leads to defects in conventional Golgi-mediated exocytosis and cell surface expression. We report that ΔF508-CFTR surface expression can be rescued in vitro and in vivo by directing it to an unconventional GRASP-dependent secretion pathway. An integrated molecular and physiological analysis indicates that mechanisms associated with ER stress induce cell surface trafficking of the ER core-glycosylated wild-type and ΔF508-CFTR via the GRASP-dependent pathway. Phosphorylation of a specific site of GRASP and the PDZ-based interaction between GRASP and CFTR are critical for this unconventional surface trafficking. Remarkably, transgenic expression of GRASP in ΔF508-CFTR mice restores CFTR function and rescues mouse survival without apparent toxicity. These findings provide insight into how unconventional protein secretion is activated, and offer a potential therapeutic strategy for the treatment of cystic fibrosis and perhaps diseases stemming from other misfolded proteins.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
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Regulador de Condutância Transmembrana em Fibrose Cística
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Via Secretória
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Proteínas de Membrana
Limite:
Animals
Idioma:
En
Revista:
Cell
Ano de publicação:
2011
Tipo de documento:
Article