Author response: Unravelling druggable signalling networks that control F508del-CFTR proteostasis

Cystic fibrosis is a genetic disease that commonly affects people of European descent. The condition is caused by mutations in the gene encoding a protein called “cystic fibrosis transmembrane conductance regulator” (or CFTR for short). CFTR forms a channel in the membrane of cells in the lungs that help transport salt across the membrane. Mutated versions of the protein are not as efficient at transporting salts, and eventually this damages the lung tissue. As the damage progresses, individuals become very vulnerable to bacterial infections that further damage the lungs and may eventually lead to death. One of the reasons CFTR mutations are harmful is that they cause the protein to fold up incorrectly and remain trapped inside the cell. Cells have quality control systems that recognize and destroy poorly folded proteins, and so only a few of the mutated CFTR proteins ever make it to the membrane to move salts. New therapies have been developed that improve folding of the protein and/or help the CFTR proteins that make it to the membrane work better. But more and better treatment options are needed. Hegde, Parashuraman et al. have now tested drugs that control how proteins fold and move to the membrane to see how they affect gene expression in cells with the most common cystic fibrosis-causing mutation. These drugs are known to improve the activity of the CFTR mutant, but do so too weakly to be of clinical interest. The experiments revealed that the expression of a few hundred genes was changed in response the drugs. Many of these genes were involved in major signalling pathways that control how CFTR is folded and trafficked within cells. Next, Hegde, Parashuraman et al. tested drugs that inhibit these signalling pathways to see if they improve salt handling in the mutated cells. The experiments demonstrated that these inhibitor drugs efficiently block the breakdown of misfolded CFTR, or boost the likelihood of CFTR making it to the membrane, helping improve salt trafficking in the cells. The inhibitors produced even better results when used in combination with a known CFTR-protecting drug. The results suggest that identifying and targeting signalling pathways involved in the folding, trafficking, and breakdown of CFTR may prove a promising way to treat cystic fibrosis.

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