Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific...

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in the CFTR gene.
• Pharmacological chaperones (correctors) like VX-809, VX-661, and VX-445 stabilize CFTR, improving folding and cell surface trafficking.
• CFTR variants exhibit differential responses to corrector treatments.

Approach:

• Investigated cellular mechanisms of CFTR biogenesis affected by correctors in P67L and L206W variants.
• Utilized affinity purification-mass spectrometry (AP-MS) with TMT labeling to quantify CFTR protein-protein interactions.
• Examined the impact of proteostasis factor knockdown on CFTR variant correction.

Key Points:

• CFTR variants P67L and L206W responded similarly to VX-809 but differently to VX-445, with P67L showing minimal rescue.
• VX-445 induced unique proteostasis factor interactions in a variant-dependent manner, affecting translation, folding, and degradation.
• Knockdown of specific interacting proteins, including ribosomal subunits, partially rescued P67L-CFTR and sensitized it to VX-445.

Conclusions:

• The study elucidates VX-445's mechanism of action, highlighting its variant-specific proteostasis interactions.
• Identified cellular targets that can potentially sensitize unresponsive CFTR variants to existing correctors.
• Provides insights for developing strategies to improve therapeutic responses for diverse CFTR mutations.