The anion transporter SLC26A9 localizes to tight ȷunctions and is degraded by the proteasome when co-expressed with F508del-CFTR [Molecular Bases of Disease]

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) disrupt epithelial secretion and cause cystic fibrosis (CF). Available CFTR modulators provide only modest clinical benefits, so alternative therapeutic targets are being explored. The anion-conducting transporter solute carrier family 26 member 9 (SLC26A9) is a promising candidate, but its functional expression is drastically reduced in cells that express the most common CF-associated CFTR variant, F508del–CFTR, through mechanisms that remain incompletely understood. Here, we examined the metabolic stability and location of SLC26A9 and its relationship to CFTR. Compared with SLC26A9 levels in BHK cells expressing SLC26A9 alone or with WT–CFTR, co-expression of SLC26A9 with F508del–CFTR reduced total and plasma membrane levels of SLC26A9. Proteasome inhibitors increased SLC26A9 immunofluorescence in primary human bronchial epithelial cells (pHBEs) homozygous for F508del–CFTR but not in non-CF pHBEs, suggesting that F508del–CFTR enhances proteasomal SLC26A9 degradation. Apical SLC26A9 expression increased when F508del–CFTR trafficking was partially corrected by low temperature or with the CFTR modulator VX-809. The immature glycoforms of SLC26A9 and CFTR co-immunoprecipitated, consistent with their interaction in the endoplasmic reticulum (ER). Transfection with increasing amounts of WT–CFTR cDNA progressively increased SLC26A9 levels in F508del–CFTR-expressing cells, ...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Membrane Biology Source Type: research