Revisiting CFTR Interactions: Old Partners and New Players

Abstract

Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key. With the availability of CFTR modulators, there is interest in comprehending which interactions are critical to rescue CFTR and which are altered by modulators or CFTR mutations. Here, the current knowledge on interactions that govern CFTR folding, processing, and stability is summarized. Furthermore, we describe protein complexes and signal pathways that modulate the CFTR function. Primary epithelial cells display a spatial control of the CFTR interactions and have become a common system for preclinical and personalized medicine studies. Strikingly, the novel roles of CFTR in development and differentiation have been recently uncovered and it has been revealed that specific CFTR gene interactions also play an important role in transcriptional regulation. For a comprehensive understanding of the molecular environment of CFTR, it is important to consider CFTR mutation-dependent interactions as well as factors affecting the CFTR interactome on the cell type, tissue-specific, and transcriptional levels.

Development and validation of a prognosis prediction model based on 18 endoplasmic reticulum stress-related genes for patients with lung adenocarcinoma

“…A recent study demonstrated that NR3C2 suppresses colon cancer progression by inhibiting the AKT/ERK pathway ( 30 ). CFTR (cystic fibrosis transmembrane conductance regulator), which belongs to the ATP-binding cassette transporter superfamily, regulates several fundamental cellular processes, including development and epithelial differentiation ( 31 ). Studies reported that CFTR acts as a tumor suppressor and is downregulated in lung cancer ( 32 ), and dysfunctional CFTR is associated with cancer progression ( 33 ).…”

From CFTR to a CF signalling network: a systems biology approach to study Cystic Fibrosis

“…However, CF symptoms not only result from the loss of CFTR-mediated anion conductance, but also from perturbations of other CFTR-dependent biological functions (Hanssens et al, 2021). Indeed, CFTR belongs to a protein-protein interactions (PPI) network (Pereira et al, 2021; Farinha and Gentzsch, 2021), and the absence of CFTR may perturb its direct or indirect interactors, and propagate dysregulations towards various biological pathways in which these interactors play a role. In agreement with this idea, studies on CFTR -/- knockout mice (Crites et al, 2015), CFTR -/- knockout piglets (Fleurot et al, 2022), and cell lines in which CFTR is inactivated by the CRISPR/Cas9 technology (Hao et al, 2020) have reported that the absence of CFTR affects cell signalling and transcriptional regulation.…”

Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters

“…CFTR protein partners have been intensively studied, enabling a better understanding of the cellular processes leading to proper protein folding, its transport to the plasma membrane, recycling and degradation. Numerous protein partners implicated in these different steps have been identified (reviewed in this special edition [ 3 ]). They have often been identified based on the comparison between WT-CFTR and the CFTR-F508del mutant [ 4 , 5 ], the most frequent CF-causing mutation, or other misfolded mutants [ 6 , 7 ].…”

“…It has been proposed that proper folding of CFTR reduces the accessibility to RXR motifs, favoring the ER exit of correctly folded channels [ 10 , 11 , 12 ]. After complex glycosylation in the Golgi apparatus, CFTR is exported to the plasma membrane where it associates with different types of proteins, such as membrane anchoring proteins, which link the channel to the cytoskeleton, or endosomal proteins implicated in the vesicular recycling of CFTR [ 3 , 13 ]. As in the ER, a peripheral quality control system monitors protein quality and targets altered channels to lysosomal degradation [ 14 , 15 ].…”