The bidirectional relationship between CFTR and lipids

Abstract

Cystic Fibrosis (CF) is the most common life-shortening genetic disease among Caucasians, resulting from mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). While work to understand this protein has resulted in new treatment strategies, it is important to emphasize that CFTR exists within a complex lipid bilayera concept largely overlooked when performing structural and functional studies. In this review we discuss cellular lipid imbalances in CF, mechanisms by which lipids affect membrane protein activity, and the specific impact of detergents and lipids on CFTR function. C ystic Fibrosis (CF) affects more than 70,000 individuals worldwide. Currently, lung failure is the leading cause of death, although many patients suffer from pancreatic insufficiency, wherein digestive enzymes are not delivered from the pancreas to the gastrointestinal tract 1. In 1989, the gene and protein associated with CF were identified and named the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) 2,3. CFTR is a member of the ATP-Binding Cassette Transporter superfamily (ABCC7). However, whereas all other ABC transporters use ATP to power an enzymatic function, CFTR is the only ABC transporter that functions primarily as an ion channel. Specifically, CFTR conducts chloride and bicarbonate. CFTR's domain architecture includes two transmembrane domains (each with six transmembrane helices (TMs)), two nucleotide binding domains, and a regulatory R-region (Fig. 1). Opening of the CFTR channel requires phosphorylation of the R-region by protein kinase A (PKA) and binding and subsequent hydrolysis of ATP at the nucleotide binding domains 4. Interestingly, the entirety of CFTR is sensitive to mutation, with some 2000 genetic variants having been described. However, F508del-CFTR is by far the most common variant, with ã 70% allele frequency in U.S. patients (https://www.cftr2.org/). Even the ultimate effect of these mutations on CFTR is complex, which is why seven different classes of mutations have been described (Table 1) 5,6. For a subset of these mutations, small-molecule therapeutics exist that increase the activity of CFTR. The first FDA-approved drug, VX-770 (Ivacaftor, KALYDECO ®) 7 , is a gating potentiator that helps certain CFTR mutants conduct more chloride upon activation by sub-maximal phosphorylation 8. The second drug, VX-809 (Lumacaftor), is a trafficking corrector that helps certain CFTR mutants reach the cell membrane 9. Lumacaftor is only ever administered in

Alteration of Membrane Cholesterol Content Plays a Key Role in Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Channel Activity

“…The accumulated evidence suggests two potential interactions between cholesterol metabolism and CFTR mutations ( Cottrill et al, 2020 ). One proposed mechanism is that CFTR mutation causes a defect in cholesterol metabolism.…”

Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes?

“…CFTR has its function in lipid structures, and lipid abnormalities have been associated with the disease for more than 50 years [ 23 ], but the interest to find treatment modalities in this field has not been encouraged. However, in recent years an increasing interest has focused on the bidirectional relation between proteins and lipids [ 24 , 25 , 26 ], also in relation to CFTR [ 27 , 28 , 29 , 30 ], and lately, the interaction between the modern CFTR modulators and membrane lipids have been shown [ 31 ].…”

Proteomics and Metabolomics for Cystic Fibrosis Research

“…While lipids are known to affect the function and the stability of other ABC transporters [71], the relation between lipid composition and CFTR is still extensively investigated. Many lipids are known to be imbalanced in CF [72]:…”

“…While lipids are known to affect the function and the stability of other ABC transporters [ 71 ], the relation between lipid composition and CFTR is still extensively investigated. Many lipids are known to be imbalanced in CF [ 72 ]: Free fatty acids, like linoleic [ 73 ] and arachidonic acid [ 74 ], are decreased and increased in nasal epithelial cells collected from CF patients respectively. Cholesterol, regulator of plasma membrane fluidity, is increased in cells [ 75 ] and tissues [ 76 ] expressing mutant-CFTR (several mutations were studied, including F508del and G551D).…”