Unravelling druggable signalling networks that control F508del-CFTR proteostasis

Ramanath Narayana Hegde, Seetharaman Parashuraman, Francesco Iorio, Fabiana Ciciriello, Fabrizio Capuani, Annamaria Carissimo, Diego Carrella, Vincenzo Belcastro, Advait Subramanian, Laura Bounti, Maria Persico, Graeme Carlile, Luis Galietta, David Y. Thomas, Diego Di Bernardo, Alberto Luini

Research output: Contribution to journalArticlepeer-review


Cystic fibrosis (CF) is caused by mutations in CF transmembrane conductance regulator (CFTR). The most frequent mutation (F508del-CFTR) results in altered proteostasis, that is, 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.

Original languageEnglish
Publication statusPublished - Dec 23 2015


  • Cell Line
  • Cystic Fibrosis
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Enzyme Inhibitors
  • Gene Expression Profiling
  • Humans
  • Protein Folding
  • Proteolysis
  • Proteostasis Deficiencies
  • Sequence Deletion
  • Signal Transduction
  • Journal Article
  • Research Support, Non-U.S. Gov't


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