Rescue by elexacaf tor-tezacaf tor-ivacaf tor of the G1244E cystic fibrosis mutation's stability and gating defects are dependent on cell background

Background: Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or ac- tivity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator.Methods: By using molecular, biochemical and functional analyses we performed an in-depth characteri- zation of the G1244E-CFTR mutant in heterologous and native cell models.Results: Our studies demonstrate that processing and function of the mutant protein, as well as its phar- macological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma mem- brane.Conclusions: Our study highlights the importance of the cell background in the evaluation of CFTR mod- ulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with se- vere gating defect.& COPY; 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.