Increased NF-κB Activity and Decreased Wnt/β-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice

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.

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Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis

Gastroenterology ◽

10.1053/j.gastro.2014.11.002 ◽

2015 ◽

Vol 148 (2) ◽

pp. 427-439.e16 ◽

Cited By ~ 91

Author(s):

József Maléth ◽

Anita Balázs ◽

Petra Pallagi ◽

Zsolt Balla ◽

Balázs Kui ◽

...

Keyword(s):

Cystic Fibrosis ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

And Function ◽

Cystic Fibrosis Transmembrane

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Comparative Processing and Function of Human and Ferret Cystic Fibrosis Transmembrane Conductance Regulator

Journal of Biological Chemistry ◽

10.1074/jbc.m111.336537 ◽

2012 ◽

Vol 287 (26) ◽

pp. 21673-21685 ◽

Cited By ~ 24

Author(s):

John T. Fisher ◽

Xiaoming Liu ◽

Ziying Yan ◽

Meihui Luo ◽

Yulong Zhang ◽

...

Keyword(s):

Cystic Fibrosis ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Comparative Processing ◽

And Function ◽

Cystic Fibrosis Transmembrane

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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis

Pharmaceuticals ◽

10.3390/ph13040075 ◽

2020 ◽

Vol 13 (4) ◽

pp. 75 ◽

Cited By ~ 2

Author(s):

Ryosuke Fukuda ◽

Tsukasa Okiyoneda

Keyword(s):

Cystic Fibrosis ◽

Structural Stability ◽

Interacting Proteins ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Surrounding Environment ◽

Cftr Protein ◽

The Stability ◽

And Function ◽

Cystic Fibrosis Transmembrane

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF).

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