Cross-talk between CFTR and sphingolipids in cystic fibrosis

Abstract

Cystic fibrosis (CF) is the most common inherited, life-limiting disorder in Caucasian populations. It is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to an impairment of protein expression and/or function. CFTR is a chloride/bicarbonate channel expressed at the apical surface of epithelial cells of different organs. Nowadays, more than 2100 CFTR genetic variants have been described, but not all of them cause CF. However, around 80-85% of the patients worldwide are characterized by the presence, at least in one allele, of the mutation F508del. CFTR mutations cause aberrant hydration and secretion of mucus in hollow organs. In the lungs, this condition favors bacterial colonization, allowing the development of chronic infections that lead to the onset of the CF lung disease, which is the main cause of death in patients. In recent years, evidence has reported that CFTR loss of function is responsible for alterations in a particular class of bioactive lipids, called sphingolipids (SL). SL are ubiquitously present in eukaryotic cells and are mainly asymmetrically located within the external leaflet of the plasma membrane, where they organize specific platforms capable of segregating a selected number of proteins. CFTR is associated with these platforms that are fundamental for its functioning. Considering the importance of SL in CFTR homeostasis, we attempt here to provide a critical overview of the literature to determine the role of these lipids in channel stability and activity, and whether their modulation in CF could be a target for new therapeutic approaches.

Keywords: CFTR; cystic fibrosis; gangliosides; metabolism; plasma membrane; sphingolipids.

Fig. 1

Structure of the main representative sphingolipid types.

Fig. 2

Schematic representation of WT‐CFTR associated with lipids rafts.

Fig. 3

Schematic representation of SL modifications in the PM of HBE cells carrying the F508del and their effect on PM instability of the mutated CFTR rescued by the CFTR modulators.

Fig. 4

Schematic representation of how the addition of ganglioside GM1 at the PM of bronchial epithelial cells carrying the F508del can ameliorate the PM instability on the mutated CFTR rescued by the CFTR modulators.