Cystic Fibrosis Transmembrane Conductance Regulator proteostasis network (CFTR proteostasis network)

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteostasis network is a sophisticated cellular system comprising hundreds of chaperones, co-chaperones, and enzymes that collectively manage the biogenesis, folding, trafficking, and degradation of the CFTR protein (Pankow et al., 2015; Balch et al., 2008). In patients with Cystic Fibrosis, particularly those harboring the common F508del mutation, the CFTR protein is recognized as misfolded by the endoplasmic reticulum-associated degradation (ERAD) machinery and is destroyed before reaching the cell surface (Amaral, 2014). The proteostasis network serves as a therapeutic target where small molecules, known as correctors or proteostasis regulators, are used to stabilize the mutant protein's conformation or modulate the network's components to favor folding over degradation (Wang et al., 2006). By enhancing the folding environment, these therapies allow functional CFTR to reach the plasma membrane, thereby restoring chloride and bicarbonate transport in epithelial tissues (Lopes-Pacheco, 2020). This network-based approach is central to the development of highly effective modulator therapies that have transformed the treatment landscape for Cystic Fibrosis (Vertex Pharmaceuticals, 2023).

Other names

CFTR interactomeCFTR folding environmentCFTR protein quality control systemCFTR-PQC

Pharmacological chaperoning to stabilize CFTR protein folding and modulation of the cellular proteostasis environment to reduce endoplasmic reticulum-associated degradation (ERAD) and promote plasma membrane trafficking.