FKBP10 depletion enhances glucocerebrosidase proteostasis in Gaucher disease fibroblasts.
Chem Biol
; 20(3): 403-15, 2013 Mar 21.
Article
em En
| MEDLINE
| ID: mdl-23434032
ABSTRACT
Lysosomal storage diseases (LSDs) are often caused by mutations compromising lysosomal enzyme folding in the endoplasmic reticulum (ER), leading to degradation and loss of function. Mass spectrometry analysis of Gaucher fibroblasts treated with mechanistically distinct molecules that increase LSD enzyme folding, trafficking, and function resulted in the identification of nine commonly downregulated and two jointly upregulated proteins, which we hypothesized would be critical proteostasis network components for ameliorating loss-of-function diseases. LIMP-2 and FK506 binding protein 10 (FKBP10) were validated as such herein. Increased FKBP10 levels accelerated mutant glucocerebrosidase degradation over folding and trafficking, whereas decreased ER FKBP10 concentration led to more LSD enzyme partitioning into the calnexin profolding pathway, enhancing folding and activity to levels thought to ameliorate LSDs. Thus, targeting FKBP10 appears to be a heretofore unrecognized therapeutic strategy to ameliorate LSDs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a Tacrolimo
/
Fibroblastos
/
Doença de Gaucher
/
Glucosilceramidase
/
Homeostase
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Chem Biol
Ano de publicação:
2013
Tipo de documento:
Article