Abstract
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.
Highlights
Cystic Fibrosis (CF) is a genetic autosomal recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene, which leads to impaired ion transport in the epithelial cells of several organs including lung, pancreas, liver and gut
We demonstrated that GM1 is reduced in CF cells (Figure 1), and that it resides in the same plasma membrane (PM) microenvironment as CFTR (Figures 2 and 4)
Using a radioactive and photoactivable GM1 derivative, we demonstrated that GM1 and CFTR reside in the same PM microenvironment in bronchial epithelial cells, and that segregation is missed in case of cells expressing F508del-CFTR (Figure 2)
Summary
Cystic Fibrosis (CF) is a genetic autosomal recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene, which leads to impaired ion transport in the epithelial cells of several organs including lung, pancreas, liver and gut. Major expression of mutated CFTR protein can be attained by using two correctors with different mechanisms of action, the efficacy was only found to be optimal when the best potentiator so far known, VX-770 (Ivacaftor), was added This triple combination, called Trikafta®, was approved by Food and Drug Administration (FDA) in October 2019, and is effective in CF patients who harbor only one copy of F508del CFTR [25]. Iimntpeorertsatnintgrolyl,eainmthoerehoimmpeoosrttaasnist oref dthuiscttiiossnuwe.as observed in differentiated HBE cells, characterized by decreased GM1 content, i.e., of nearly 80%, in pathological cells compared to WT (Figure 1b) Taken together, these results suggest that the expression of F508del-CFTR in bronchial epithelial cells may impair the levels of ganglioside GM1. The massive reduction observed in HBE, cells committed to form a bronchial epithelium led us to speculate that this ganglioside may play an important role in the homeostasis of this tissue
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