The F508del-CFTR trafficking correctors elexacaftor and tezacaftor are CFTR-independent Ca2+-mobilizing agonists normalizing abnormal Ca2+ levels in human airway epithelial cells - Archive ouverte HAL
Article Dans Une Revue Respiratory Research Année : 2024

The F508del-CFTR trafficking correctors elexacaftor and tezacaftor are CFTR-independent Ca2+-mobilizing agonists normalizing abnormal Ca2+ levels in human airway epithelial cells

Résumé

Background Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel. For people with CF (pwCF) affected by the most common pathogenic variant F508del, a tritherapy, named Trikafta/Kaftrio (ETI: elexacaftor (VX-445) /tezacaftor (VX-661) / ivacaftor (VX-770)) was successfully developed. However, in CF airway epithelial cells the calcium homeostasis is also disturbed; it is observed an increased calcium mobilization in CF cells compared to non-CF cells. Here, we studied the effects of ETI on intracellular calcium levels in F508del-CFTR airway epithelial cells to determine whether these compounds, individually or collectively, could normalize intracellular calcium levels.

Methods

We measured intracellular calcium variations using human airway epithelial cells (hAEC) from pwCF, human bronchial epithelial CFBE41o-F508del-CFTR cells and Chinese Hamster Ovary (CHO) cells using the fluorescent probe Fluo4-AM, in the presence or absence of extracellular calcium. The rescue to the plasma membrane of F508del-CFTR protein by ETI was determined by western blot. The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA), was also analysed by western blotting and by interference assay.

Results

We show that ETI normalizes calcium homeostasis in our cellular models. However, we also found that (1) each ETI-corrector compound is capable of mobilizing calcium acutely in the absence of CFTR, and (2) tezacaftor mobilizes calcium from the endoplasmic reticulum (ER) probably via inhibition of the SERCA pump. Conclusions We show that ETI not only corrects the abnormal trafficking and function of F508del-CFTR but also normalizes calcium homeostasis in our cellular models. Finally, we identified SERCA as a potential intracellular target for tezacaftor.

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Dates et versions

hal-04852924 , version 1 (21-12-2024)

Identifiants

Citer

Manuella Lévêque, Sandra Mirval, Christine Barrault, Isabelle Fixe, Christelle Coraux, et al.. The F508del-CFTR trafficking correctors elexacaftor and tezacaftor are CFTR-independent Ca2+-mobilizing agonists normalizing abnormal Ca2+ levels in human airway epithelial cells. Respiratory Research, 2024, 25 (1), pp.436. ⟨10.1186/s12931-024-03059-8⟩. ⟨hal-04852924⟩
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