Abstract
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.
Highlights
In the present work we demonstrated the synergistic effect of SLC26A9 expression levels on CFTR expression and function, and most importantly, on the rescue of F508delCFTR by the highly effective modulator therapy (HEMT) currently available in the clinic (VX-661 + VX-445)
Consistent with previous data [27], our data show that SLC26A9 and CFTR seem to co-localize in native human bronchial epithelia, either in samples from a non-Cystic Fibrosis (CF) individual at the PM
The co-localization of SLC26A9 and CFTR has been assessed mostly through their heterologous expression either in HEK293T or CFBE41o-cells transfected with tagged SLC26A9 constructs [25,26,28], recently the same was shown in welldifferentiated primary human bronchial epithelial cell cultures [27]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cystic Fibrosis (CF), a life-shortening genetic disorder affecting ~90,000 individuals worldwide [1], is caused by mutations in the CFTR Conductance Regulator) gene [2], which encodes a cAMP-regulated chloride (Cl− ) and bicarbonate (HCO3 − ) channel expressed at the apical plasma membrane (PM) of epithelial cells [3]. Defective CFTR leads to an imbalance in salt and fluid transport that results in dehydrated and viscous secretions. CF is a multi-organ disease, affecting the intestine, pancreas, and reproductive tract, but the lungs are the most critically affected organ. Lung failure is the main cause of mortality and morbidity in individuals with CF [4–6]
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