Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.
Cell
; 127(4): 803-15, 2006 Nov 17.
Article
en En
| MEDLINE
| ID: mdl-17110338
The pathways that distinguish transport of folded and misfolded cargo through the exocytic (secretory) pathway of eukaryotic cells remain unknown. Using proteomics to assess global cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein interactions (the CFTR interactome), we show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein folding in the endoplasmic reticulum (ER). Cell-surface rescue of the most common disease variant that is restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1. We propose that failure of DeltaF508 to achieve an energetically favorable fold in response to the steady-state dynamics of the chaperone folding environment (the "chaperome") is responsible for the pathophysiology of CF. The activity of cargo-associated chaperome components may be a common mechanism regulating folding for ER exit, providing a general framework for correction of misfolding disease.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Regulación hacia Abajo
/
Pliegue de Proteína
/
Chaperonas Moleculares
/
Proteínas HSP90 de Choque Térmico
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Regulador de Conductancia de Transmembrana de Fibrosis Quística
/
Fibrosis Quística
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos