Regulation of CFTR stability at the plasma membrane—Mechanisms and therapeutic opportunities in cystic fibrosis

CFTR stability at the plasma membrane is controlled by a dynamic balance between trafficking, endocytosis, recycling, and degradation. Interactions with scaffold proteins such as NHERF1 and ezrin anchor CFTR to the actin cytoskeleton, reducing mobility and enhancing stability. Cytoskeletal dynamics, regulated by GTPases like RhoA, Rac1, and Rap1, further influence CFTR retention and function. Phosphorylation by kinases including PKA, LMTK2, and SYK modulates channel activity and membrane presence. Whereas rescue of F508del-CFTR with modulators can rescue its defective folding and premature degradation, reduced membrane stability persists. Overall, understanding the molecular mechanisms governing CFTR regulation provides critical insights for developing more effective treatments targeting its stability and function in cystic fibrosis.