scholarly journals Regulation of CFTR Biogenesis by the Proteostatic Network and Pharmacological Modulators

2020 ◽  
Vol 21 (2) ◽  
pp. 452 ◽  
Author(s):  
Samuel Estabrooks ◽  
Jeffrey L. Brodsky
Keyword(s):  
Cystic Fibrosis ◽  
Common Disease ◽  
Transmembrane Conductance Regulator ◽  
Inherited Disease ◽  
Transmembrane Conductance ◽  
Gene Encoding ◽  
The Many ◽  
And Function ◽  
Cystic Fibrosis Transmembrane ◽  
Pharmacological Modulators

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.

scholarly journals Quantitative Evaluation of CFTR Pre-mRNA Splicing Dependent on the (TG)mTn Poly-Variant Tract

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 168
Author(s):  
Manuela Sterrantino ◽  
Andrea Fuso ◽  
Silvia Pierandrei ◽  
Sabina Maria Bruno ◽  
Giancarlo Testino ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Functional Effect ◽  
Transmembrane Conductance ◽  
Therapeutic Consequences ◽  
Clinical Consequences ◽  
Exon 9 ◽  
The Many ◽  
Cystic Fibrosis Transmembrane ◽  
Exon 10

Genetic analysis in cystic fibrosis (CF) is a difficult task. Within the many causes of variability and uncertainty, a major determinant is poor knowledge of the functional effect of most DNA variants of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. In turn, knowledge of the effect of a CFTR variant has dramatic diagnostic, prognostic and, in the era of CF precision medicine, also therapeutic consequences. One of the most challenging CFTR variants is the (TG)mTn haplotype, which has variable functional effect and controversial clinical consequences. The exact quantification of the anomalous splicing of CFTR exon 10 (in the HGVS name; exon 9 in the legacy name) and, consequently, of the residual wild-type functional CFTR mRNA, should be mandatory in clinical assessment of patients with potentially pathological haplotype of this tract. Here, we present a real time-based assay for the quantification of the proportion of exon 10+/exon 10− CFTR mRNA, starting from nasal brushing. Our assay proved rapid, economic and easy to perform. Specific primers used for this assay are either disclosed or commercially available, allowing any laboratory to easily perform it. A simplified analysis of the data is provided, facilitating the interpretation of the results. This method helps to enhance the comprehension of the genotype–phenotype relationship in CF and CFTR-related disorders (CFTR-RD), crucial for the diagnosis, prognosis and personalized therapy of CF.

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

2015 ◽  
Vol 148 (2) ◽  
pp. 427-439.e16 ◽  
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

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

2012 ◽  
Vol 287 (26) ◽  
pp. 21673-21685 ◽  
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

scholarly journals Cytoskeleton regulators CAPZA2 and INF2 associate with CFTR to control its plasma membrane levels under EPAC1 activation

2020 ◽  
Vol 477 (13) ◽  
pp. 2561-2580
Author(s):  
João D. Santos ◽  
Francisco R. Pinto ◽  
João F. Ferreira ◽  
Margarida D. Amaral ◽  
Manuela Zaccolo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein A ◽  
Bioinformatic Analysis ◽  
Apical Surface ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Gene Encoding ◽  
Cftr Protein ◽  
Related Proteins ◽  
Cystic Fibrosis Transmembrane

Cystic Fibrosis (CF), the most common lethal autosomic recessive disorder among Caucasians, is caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, a cAMP-regulated chloride channel expressed at the apical surface of epithelial cells. Cyclic AMP regulates both CFTR channel gating through a protein kinase A (PKA)-dependent process and plasma membane (PM) stability through activation of the exchange protein directly activated by cAMP1 (EPAC1). This cAMP effector, when activated promotes the NHERF1:CFTR interaction leading to an increase in CFTR at the PM by decreasing its endocytosis. Here, we used protein interaction profiling and bioinformatic analysis to identify proteins that interact with CFTR under EPAC1 activation as possible regulators of this CFTR PM anchoring. We identified an enrichment in cytoskeleton related proteins among which we characterized CAPZA2 and INF2 as regulators of CFTR trafficking to the PM. We found that CAPZA2 promotes wt-CFTR trafficking under EPAC1 activation at the PM whereas reduction of INF2 levels leads to a similar trafficking promotion effect. These results suggest that CAPZA2 is a positive regulator and INF2 a negative one for the increase of CFTR at the PM after an increase of cAMP and concomitant EPAC1 activation. Identifying the specific interactions involving CFTR and elicited by EPAC1 activation provides novel insights into late CFTR trafficking, insertion and/or stabilization at the PM and highlighs new potential therapeutic targets to tackle CF disease.

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

2020 ◽  
Vol 13 (4) ◽  
pp. 75 ◽  
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).

scholarly journals Production of CFTR-ΔF508 Rabbits

2021 ◽  
Vol 11 ◽  
Author(s):  
Dongshan Yang ◽  
Xiubin Liang ◽  
Brooke Pallas ◽  
Mark Hoenerhoff ◽  
Zhuoying Ren ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Autosomal Recessive ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Germline Transmission ◽  
Transmembrane Conductance ◽  
Gene Encoding ◽  
Cystic Fibrosis Transmembrane ◽  
Phenylalanine Residue ◽  
F1 Generation

Cystic Fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation is the deletion of phenylalanine residue at position 508 (ΔF508). Here we report the production of CFTR-ΔF508 rabbits by CRISPR/Cas9-mediated gene editing. After microinjection and embryo transfer, 77 kits were born, of which five carried the ΔF508 mutation. To confirm the germline transmission, one male ΔF508 founder was bred with two wild-type females and produced 16 F1 generation kits, of which six are heterozygous ΔF508/WT animals. Our work adds CFTR-ΔF508 rabbits to the toolbox of CF animal models for biomedical research.

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