Cystic fibrosis transmembrane conductance regulator proteostasis pathway (CFTR proteostasis pathway)

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteostasis pathway is a sophisticated cellular network that governs the synthesis, folding, post-translational modification, and trafficking of the CFTR protein (Farinha & Amaral, 2005). This pathway involves a suite of molecular chaperones, such as Hsp70, Hsp90, and calnexin, alongside the endoplasmic reticulum-associated degradation (ERAD) system, which identifies and targets misfolded proteins for proteasomal destruction (Balch et al., 2008). In Cystic Fibrosis, most notably in patients with the F508del mutation, the CFTR protein fails to adopt its native conformation, leading to its entrapment in the endoplasmic reticulum and subsequent degradation (Loo & Clarke, 2017). Therapeutic strategies targeting this pathway utilize correctors like Lumacaftor and Elexacaftor, which act as pharmacological chaperones to stabilize the protein structure and facilitate its escape from the quality control machinery (Wainwright et al., 2015). By restoring the balance of proteostasis, these treatments increase the density of functional chloride channels at the apical membrane of epithelial cells, thereby alleviating the clinical manifestations of the disease (Vertex Pharmaceuticals, 2023).

Other names

CFTR folding and trafficking pathwayCFTR quality control networkCFTR biosynthetic pathwayCFTR protein processing pathway

Pharmacological chaperones (correctors) bind directly to the CFTR protein to stabilize its conformation and prevent degradation, while proteostasis regulators modulate the activity of cellular chaperones and the ERAD machinery to promote successful trafficking to the plasma membrane.