Unravelling druggable signalling networks that control F508del-CFTR proteostasis

Area of Science:

• Molecular Biology
• Cell Biology
• Pharmacology

Background:

• Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene.
• The most common mutation, F508del-CFTR, leads to protein misfolding, impaired trafficking, and premature degradation, disrupting cellular proteostasis.
• While CFTR proteostasis mechanisms are known, the role of classical signaling pathways in regulating these defects is largely unexplored.

Purpose of the Study:

• To investigate the involvement of signaling pathways and phosphorylation cascades in controlling F508del-CFTR proteostasis.
• To identify novel therapeutic targets by analyzing the mechanisms of action of existing CFTR proteostasis regulator drugs.

Main Methods:

• Transcriptional profiling of cells treated with CFTR proteostasis regulator drugs.
• Deconvolution of gene signatures to identify affected signaling pathways.
• Selective targeting of identified signaling pathway components.

Main Results:

• Signaling cascades were identified that selectively correct F508del-CFTR folding and trafficking defects.
• Targeting multiple components of these pathways demonstrated potent and specific correction of CFTR proteostasis.
• Combined targeting showed synergistic effects with existing pharmacochaperone therapies.

Conclusions:

• Classical signaling pathways play a significant role in regulating F508del-CFTR proteostasis.
• Targeting these newly identified signaling cascades provides a rational basis for developing improved pharmacological correctors for CF.
• This research offers new insights into cellular proteostasis and potential therapeutic strategies for cystic fibrosis.