New insights into the role of endoplasmic reticulum-associated degradation in Bartter Syndrome Type 1.
Bartter syndrome
ERAD
NKCC2
hypertension
membrane
trafficking
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
12
04
2021
received:
10
11
2020
accepted:
30
04
2021
pubmed:
12
5
2021
medline:
1
4
2022
entrez:
11
5
2021
Statut:
ppublish
Résumé
Mutations in Na-K-2Cl co-transporter, NKCC2, lead to type I Bartter syndrome (BS1), a life-threatening kidney disease. Yet, our knowledge of the molecular regulation of NKCC2 mutants remains poor. Here, we aimed to identify the molecular pathogenic mechanisms of one novel and three previously reported missense NKCC2 mutations. Co-immunolocalization studies revealed that all NKCC2 variants are not functional because they are not expressed at the cell surface due to retention in the endoplasmic reticulum (ER). Cycloheximide chase assays together with treatment by protein degradation and mannose trimming inhibitors demonstrated that the defect in NKCC2 maturation arises from ER retention and associated degradation (ERAD). Small interfering RNA (siRNA) knock-down experiments revealed that the ER lectin OS9 is involved in the ERAD of NKCC2 mutants. 4-phenyl butyric acid (4-PBA) treatment mimicked OS9 knock-down effect on NKCC2 mutants by stabilizing their immature forms. Importantly, out of the four studied mutants, only one showed an increased protein maturation upon treatment with glycerol. In summary, our study reveals that BS1 is among diseases linked to the ERAD pathway. Moreover, our data open the possibility that maturation of some ER retained NKCC2 variants is correctable by chemical chaperones offering, therefore, promising avenues in elucidating the molecular pathways governing the ERAD of NKCC2 folding mutants.
Substances chimiques
SLC12A1 protein, human
0
Solute Carrier Family 12, Member 1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
947-968Informations de copyright
© 2021 Wiley Periodicals LLC.
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