Unravelling druggable signalling networks that control F508del-CFTR proteostasis
- National Research Council, Italy
- European Molecular Biology Laboratory, European Bioinformatics Institute, United Kingdom
- Telethon Institute of Genetics and Medicine, Italy
- University of Rome, La Sapienza, Italy
- Institute of Protein Biochemistry, Italy
- KU Leuven University, Italy
- McGill University, Canada
- Institute of Giannina Gaslini, Italy
Abstract
Cystic fibrosis (CF) is caused by mutations in CF transmembrane conductance regulator (CFTR). The most frequent mutation (F508del-CFTR) results in altered proteostasis, i.e., in the misfolding and intracellular degradation of the protein. The F508del-CFTR proteostasis machinery and its homeostatic regulation are well studied, while the question whether 'classical' signalling pathways and phosphorylation cascades might control proteostasis remains barely explored. Here, we have unravelled signalling cascades acting selectively on the F508del-CFTR folding-trafficking defects by analysing the mechanisms of action of F508del-CFTR proteostasis regulator drugs through an approach based on transcriptional profiling followed by deconvolution of their gene signatures. Targeting multiple components of these signalling pathways resulted in potent and specific correction of F508del-CFTR proteostasis and in synergy with pharmacochaperones. These results provide new insights into the physiology of cellular proteostasis and a rational basis for developing effective pharmacological correctors of the F508del-CFTR defect.
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© 2015, Hegde et al.
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Unravelling druggable signalling networks that control F508del-CFTR proteostasis
eLife 4:e10365.
https://doi.org/10.7554/eLife.10365
