Short-term consequences of F508del-CFTR thermal instability on CFTR-dependent transepithelial currents in human airway epithelial cells - Archive ouverte HAL Access content directly
Journal Articles Scientific Reports Year : 2019

Short-term consequences of F508del-CFTR thermal instability on CFTR-dependent transepithelial currents in human airway epithelial cells

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Abstract

Loss-of-function mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) channel in human airway epithelial cells are responsible for Cystic Fibrosis. A deleterious impact of physiological temperature on CFTR plasma membrane expression, residence and channel activity is characteristic of the most common and severe CF mutation, F508del. Using primary human F508del-airway epithelial cells and CF bronchial epithelial CFBE41o-cell lines expressing F508del-or WT-CFTR, we examined the effects of temperature (29 °C-39 °C) on the amplitude and stability of short-circuit CFTR-dependent currents over time and the efficiency of pharmacological strategies to stably restore F508del-CFTR function. We show that F508del-CFTR functional instability at 37 °C is not prevented by low temperature or VX-809 correction, genistein and VX-770 potentiators, nor by the combination VX-809/VX-770. Moreover, F508del-CFTR-dependent currents 30 minutes after CFTR activation at 37 °C did not significantly differ whether a potentiator was used or not. We demonstrate that F508del-CFTR function loss is aggravated at temperatures above 37 °C while limited by a small decrease of temperature and show that the more F508del-CFTR is stimulated, the faster the current loss happens. Our study highlights the existence of a temperature-dependent process inhibiting the function of F508del-CFTR, possibly explaining the low efficacy of pharmacological drugs in clinic.
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hal-02448604 , version 1 (26-05-2020)

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Lionel Froux, Christelle Coraux, Edouard Sage, Frédéric Becq. Short-term consequences of F508del-CFTR thermal instability on CFTR-dependent transepithelial currents in human airway epithelial cells. Scientific Reports, 2019, 9 (1), ⟨10.1038/s41598-019-50066-7⟩. ⟨hal-02448604⟩
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