Restoration of β-GC trafficking improves the lysosome function in Gaucher disease.
Gaucher disease
lysosome
lysosome storage diseases
phosphatome
β-glucocerebrosidase
Journal
Traffic (Copenhagen, Denmark)
ISSN: 1600-0854
Titre abrégé: Traffic
Pays: England
ID NLM: 100939340
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
04
06
2023
received:
23
06
2022
accepted:
04
07
2023
medline:
11
9
2023
pubmed:
26
7
2023
entrez:
26
7
2023
Statut:
ppublish
Résumé
Lysosomes function as a primary site for catabolism and cellular signaling. These organelles digest a variety of substrates received through endocytosis, secretion and autophagy with the help of resident acid hydrolases. Lysosomal enzymes are folded in the endoplasmic reticulum (ER) and trafficked to lysosomes via Golgi and endocytic routes. The inability of hydrolase trafficking due to mutations or mutations in its receptor or cofactor leads to cargo accumulation (storage) in lysosomes, resulting in lysosome storage disorder (LSD). In Gaucher disease (GD), the lysosomes accumulate glucosylceramide because of low β-glucocerebrosidase (β-GC) activity that causes lysosome enlargement/dysfunction. We hypothesize that improving the trafficking of mutant β-GC to lysosomes may improve the lysosome function in GD. RNAi screen using high throughput based β-GC activity assay followed by reporter trafficking assay utilizing β-GC-mCherry led to the identification of nine potential phosphatases. Depletion of these phosphatases in HeLa cells enhanced the β-GC activity by increasing the folding and trafficking of Gaucher mutants to the lysosomes. Consistently, the lysosomes in primary fibroblasts from GD patients restored their β-GC activity upon the knockdown of these phosphatases. Thus, these studies provide evidence that altering phosphatome activity is an alternative therapeutic strategy to restore the lysosome function in GD.
Substances chimiques
Glucosylceramidase
EC 3.2.1.45
Phosphoric Monoester Hydrolases
EC 3.1.3.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
489-503Informations de copyright
© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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