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Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ?F508-CFTR.


ABSTRACT: The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ?F508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased their expression levels on the cell surface and, consequently, upregulated their function. Furthermore, genetic ablation of DNAJB9 in WT mice increased CFTR expression and enhanced CFTR-dependent fluid secretion in enteroids. Importantly, DNAJB9 deficiency upregulated enteroids' fluid secretion in CF mice (homozygous for ?F508), and silencing one allele of DNAJB9 is sufficient to rescue ?F508-CFTR in vitro and in vivo, suggesting that DNAJB9 may be a rate-limiting factor in CFTR ERAD pathway. Our studies identified the first ER luminal co-chaperone involved in CFTR ERAD, and DNAJB9 could be a novel therapeutic target for CF.

SUBMITTER: Huang Y 

PROVIDER: S-EPMC6614449 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Targeting DNAJB9, a novel ER luminal co-chaperone, to rescue ΔF508-CFTR.

Huang Yunjie Y   Arora Kavisha K   Mun Kyu Shik KS   Yang Fanmuyi F   Moon ChangSuk C   Yarlagadda Sunitha S   Jegga Anil A   Weaver Timothy T   Naren Anjaparavanda P AP  

Scientific reports 20190708 1


The molecular mechanism of Endoplasmic Reticulum-associated degradation (ERAD) of Cystic fibrosis transmembrane-conductance regulator (CFTR) is largely unknown. Particularly, it is unknown what ER luminal factor(s) are involved in ERAD. Herein, we used ProtoArray to identify an ER luminal co-chaperone, DNAJB9, which can directly interact with CFTR. For both WT- and ΔF508 (deletion of phenylalanine at position 508, the most common CF-causing mutant)-CFTR, knockdown of DNAJB9 by siRNA increased th  ...[more]

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