Effects of GM1 ganglioside and its derivatives on ETI-rescued F508del-CFTR maturation and host-pathogen interactions in cystic fibrosis bronchial cells.

Abstract

Cystic Fibrosis (CF), a life-threatening hereditary disease, arises from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes a chloride-conducting channel widely expressed in epithelial cells. The most common mutation, F508del, causes CFTR misfolding, premature degradation, and impaired mucociliary clearance, leading to recurrent respiratory infections and inflammation. The triple combination therapy with Elexacaftor, Tezacaftor, and Ivacaftor (ETI) has revolutionized CF management by partially restoring mutated CFTR function. However, enhancing CFTR rescue and stabilizing host immune responses remain critical challenges. In airway epithelial cells, CFTR interacts with proteins and lipids in macromolecular complexes that influence its stability. Among these, the ganglioside GM1 plays a key role in modulating plasma membrane protein dynamics, including CFTR. This study investigates the effects of exogenous GM1 supplementation as an adjuvant to ETI treatment. Our results demonstrate that GM1 enhances F508del-CFTR maturation and stability, even under Pseudomonas aeruginosa infection, which typically suppresses CFTR expression and function. Furthermore, GM1 restores xenophagic activity in bronchial epithelial cells, improving host defence mechanisms against the bacteria. These findings underscore the therapeutic potential of GM1 and its analogues in optimizing the plasma membrane environment for CFTR correction, suggesting that by enhancing the efficacy of CFTR modulators, GM1 could pave the way for innovative approaches to improve CF management.