期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 23, 页码 -出版社
MDPI
DOI: 10.3390/ijms222313064
关键词
anion channels; CFTR; Cl- secretion; Cystic Fibrosis
资金
- FCT/ MCTES Portugal [PPBI-POCI-01-0145-FEDER-022122, UIDB/04046/2020]
- CF Trust/UK [UIDP/04046/2020]
- FCT (Portugal) [SRC 013, SFRH/PD/BD/114393/2016, SFRH/BD/142857/2018]
- [PD/00065/2012]
SLC26A9 is a constitutively active Cl- transporter that contributes to epithelial Cl- secretion and is implicated in respiratory disorders such as CF. Studies have shown that enhancing SLC26A9 expression can increase CFTR function and response to CFTR correctors, suggesting its potential as a therapeutic target for CF.
SLC26A9, a constitutively active Cl- transporter, has gained interest over the past years as a relevant disease modifier in several respiratory disorders including Cystic Fibrosis (CF), asthma, and non-CF bronchiectasis. SLC26A9 contributes to epithelial Cl- secretion, thus preventing mucus obstruction under inflammatory conditions. Additionally, SLC26A9 was identified as a CF gene modifier, and its polymorphisms were shown to correlate with the response to drugs modulating CFTR, the defective protein in CF. Here, we aimed to investigate the relationship between SLC26A9 and CFTR, and its role in CF pathogenesis. Our data show that SLC26A9 expression contributes to enhanced CFTR expression and function. While knocking-down SLC26A9 in human bronchial cells leads to lower wt- and F508del-CFTR expression, function, and response to CFTR correctors, the opposite occurs upon its overexpression, highlighting SLC26A9 relevance for CF. Accordingly, F508del-CFTR rescue by the most efficient correctors available is further enhanced by increasing SLC26A9 expression. Interestingly, SLC26A9 overexpression does not increase the PM expression of non-F508del CFTR traffic mutants, namely those unresponsive to corrector drugs. Altogether, our data indicate that SLC26A9 stabilizes CFTR at the ER level and that the efficacy of CFTR modulator drugs may be further enhanced by increasing its expression.
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