Regulation of CFTR Biogenesis by the Proteostatic Network and Pharmacological Modulators

Abstract

Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians in North America and a significant portion of Europe. The disease arises from one of many mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator, or CFTR. The most common disease-associated allele, F508del, along with several other mutations affect the folding, transport, and stability of CFTR as it transits from the endoplasmic reticulum (ER) to the plasma membrane, where it functions primarily as a chloride channel. Early data demonstrated that F508del CFTR is selected for ER associated degradation (ERAD), a pathway in which misfolded proteins are recognized by ER-associated molecular chaperones, ubiquitinated, and delivered to the proteasome for degradation. Later studies showed that F508del CFTR that is rescued from ERAD and folds can alternatively be selected for enhanced endocytosis and lysosomal degradation. A number of other disease-causing mutations in CFTR also undergo these events. Fortunately, pharmacological modulators of CFTR biogenesis can repair CFTR, permitting its folding, escape from ERAD, and function at the cell surface. In this article, we review the many cellular checkpoints that monitor CFTR biogenesis, discuss the emergence of effective treatments for CF, and highlight future areas of research on the proteostatic control of CFTR.

Choice of Differentiation Media Significantly Impacts Cell Lineage and Response to CFTR Modulators in Fully Differentiated Primary Cultures of Cystic Fibrosis Human Airway Epithelial Cells

“…In the literature, the transcriptional and post-transcriptional CFTR regulation pathway is well described [ 88 ]. Misfolded F508del-CFTR is sequestered in the ER and then degraded through the ER-associated degradation (ERAD) pathway, which involves many co-chaperones [ 89 ]. Although our RNA-seq data revealed that a number of proteins that interact with CFTR were differentially regulated in UNC- and SC-grown epithelia ( Table S6 ), it is unclear whether enhanced protein degradation via ERAD could account for our results.…”

Current Treatment Options for Cystic Fibrosis-Related Liver Disease

“…It belongs to the family of ATP-binding cassette (ABC) transporters (CFTR is alternately known as ABC subfamily C member 7 (ABCC7)) and functions as a cyclic adenosine monophosphate (cAMP)-dependent chloride channel that may open on the cell surface of epithelial cells. This chloride channel is necessary to maintain an alkaline pH and dilute fluid secretions [ 4 ] via a passive Cl − /HCO3 − anion exchange on exocrine epithelia along their electrochemical gradient [ 5 , 6 ]. Defects of CFTR may lead to dehydration of secretions and hyperviscous mucus, causing a multisystem disease with major affections of the respiratory, gastrointestinal, and hepatobiliary tract.…”

CFTR corrector efficacy is associated with occupancy of distinct binding sites

“…Early on, the folding defect associated with F508del was shown to be partially rescued by incubating the cells at 27°C (6), which is believed to stabilize key limiting folding intermediates and lead to the partial maturation of the protein. Rescue could also be achieved with small molecules such as chemical chaperones, one of the best examples being glycerol (7). These observations led to the screening of small molecules favoring the proper folding of mutant CFTR and to the identification of drugs named correctors, such as VX-809 (Lumacaftor) or its structurally closely related analogue VX-661 (Tezacaftor).…”