Related Experiment Video
Updated: Jul 16, 2025
07:04
Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients
Published on: February 11, 2017
19.3K
Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific
Minsoo Kim1, Eli Fritz McDonald2, Carleen Mae P Sabusap2
1Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA; Program in Chemical and Physical Biology, Vanderbilt University, Nashville, Tennessee, USA.
The Journal of Biological Chemistry
|September 10, 2023
Summary
Elexacaftor (VX-445) shows variant-specific effects on cystic fibrosis transmembrane conductance regulator (CFTR) protein. Targeting translation and protein folding pathways can improve VX-445 efficacy in nonresponsive CFTR variants like P67L.
Area of Science:
- Molecular Biology
- Genetics
- Pharmacology
Background:
- Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in the CFTR gene.
- CFTR correctors, like elexacaftor (VX-445), stabilize and improve CFTR protein processing.
- CFTR variants exhibit differential responses to corrector therapies.
Purpose of the Study:
- To investigate the differential response of CFTR variants P67L and L206W to VX-445.
- To elucidate the cellular mechanisms underlying CFTR biogenesis and corrector efficacy.
- To identify potential targets for sensitizing nonresponsive CFTR variants to VX-445.
Main Methods:
- Affinity purification-mass spectrometry with isobaric tandem mass tags to analyze CFTR protein-protein interactions.
- siRNA knockdown of interacting proteins, including ribosomal subunit proteins.
- Partial inhibition of protein translation.
Main Results:
- VX-445 demonstrated variant-dependent interactions with proteostasis factors involved in translation, folding, and degradation.
- Knockdown of specific interacting proteins, such as ribosomal proteins, partially rescued P67L CFTR.
- These knockdowns sensitized P67L CFTR to VX-445, enhancing trafficking correction.
- Partial inhibition of protein translation also improved P67L CFTR response to VX-445.
Conclusions:
- VX-445's mechanism of action is influenced by CFTR variant-specific proteostasis networks.
- Targeting protein translation and folding pathways can enhance the efficacy of VX-445 for nonresponsive CFTR variants.
- This study identifies potential cellular targets to improve corrector therapy for CF patients with specific mutations.
Related Concept Videos
01:23Cystic Fibrosis: Pathogenesis
275
Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
275
01:24Cystic Fibrosis: Management
191
Cystic fibrosis (CF) is an autosomal recessive disorder that predominantly affects individuals of Northern European descent, occurring at a rate of 1 in 3500. It is caused by a genetic mutation in a gene on chromosome 7, most commonly the ΔF508 mutation, that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This results in thicker mucus secretions and obstruction pathologies in multiple organs, including the lungs and sinuses.
Sinus disease and chronic...
Sinus disease and chronic...
191
01:57Protein Complexes with Interchangeable Parts
2.6K
Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
2.6K
02:28Leaky Scanning
5.2K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.2K