Institute of Protein Biochemistry, National Research Council, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Seetharaman Parashuraman
Institute of Protein Biochemistry, National Research Council, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Francesco Iorio
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Fabiana Ciciriello
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Biology and Biotechnology Department "Charles Darwin", Sapienza University, Rome, Italy; Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada
Fabrizio Capuani
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Annamaria Carissimo
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Diego Carrella
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Vincenzo Belcastro
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Advait Subramanian
Institute of Protein Biochemistry, National Research Council, Naples, Italy
Laura Bounti
Institute of Protein Biochemistry, National Research Council, Naples, Italy
Maria Persico
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
Graeme Carlile
Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada
Luis Galietta
U.O.C. Genetica Medica, Institute of Giannina Gaslini, Genova, Italy
David Y Thomas
Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada
Diego Di Bernardo
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy
Alberto Luini
Institute of Protein Biochemistry, National Research Council, Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Istituto di Ricovero e Cura a Carattere Scientifico SDN, Naples, Italy
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.
