Synergy in Cystic Fibrosis Therapies: Targeting SLC26A9

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.

Expression of SLC26A9 in Airways and Its Potential Role in Asthma

“…We speculate that the airway epithelium in these rare lung sections was not fully differentiated, possibly due to inflammation. Importantly, SLC26A9 was only found in ciliated epithelial cells, which corresponds well to the interaction of SLC26A9 and other SLC26A solute transporters with CFTR, as described in several previous reports [ 9 , 14 , 27 , 28 , 29 , 30 ].…”

SLC26A9 as a Potential Modifier and Therapeutic Target in Cystic Fibrosis Lung Disease

“…Besides different studies seem to indicate a relevant role of this protein in the gastrointestinal tract, the contribution of SLC26A9 to the lung function is still elusive, highlighting the need for further investigations. For example, despite a few studies reporting some SLC26A9 expression in human bronchial airways [18,24], others have failed to find relevant expression or detected SLC26A9 only in a small fraction of The cartoon shows a simplified airway epithelial cell model with some of the various transporters, channels, and exchangers involved in ion secretion mechanisms. Among these, SLC26A9 could be potentially targeted to circumvent the reduced chloride secretion due to the loss of function of CFTR by searching for small molecules acting as activators or potentiators of its ion transport activity.…”

“…Besides these findings, not much more effort has been made in the characterization of SLC26A9 protein expression in human airway tissue, until the very recent work by Pinto and colleagues [ 24 ]. These authors found some SLC26A9-positive signals by immunofluorescence on native human bronchial tissues (by using a commercially available antibody, NBP2-30425) [ 24 ].…”

“…Besides these findings, not much more effort has been made in the characterization of SLC26A9 protein expression in human airway tissue, until the very recent work by Pinto and colleagues [ 24 ]. These authors found some SLC26A9-positive signals by immunofluorescence on native human bronchial tissues (by using a commercially available antibody, NBP2-30425) [ 24 ]. SLC26A9 appeared localized in the apical pole of bronchial epithelial cells, possibly overlapping CFTR and the tight junction marker ZO-1, in control tissues, whereas showed cytoplasmic staining in tissues from CF donors carrying F508del-CFTR [ 24 ].…”

“…Concerning CFTR activity, the co-transfection of SLC26A9 and wt-CFTR in HEK-293 cells resulted in enhanced forskolin-stimulated CFTR-dependent current [ 28 ]. Importantly, in immortalized human bronchial epithelial cell lines (CFBE41o − and 16HBE14o − ), SLC26A9 overexpression and silencing resulted in increased and reduced CFTR expression and function, respectively [ 24 ].…”