title: Unravelling druggable signalling networks that control F508del-CFTR proteostasis.
abstract: 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.
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.|Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Ramanath Narayana
authors.identifier: http://orcid.org/0000-0001-7224-3544
authors.initials: RN
authors.lastname: Hegde
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.|Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Parashuraman
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: 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.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ciciriello
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Capuani
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Carissimo
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Carrella
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Belcastro
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Advait
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bounti
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Persico
authors.affiliation: Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada.
authors.forename: Graeme
authors.initials: G
authors.lastname: Carlile
authors.affiliation: U.O.C. Genetica Medica, Institute of Giannina Gaslini, Genova, Italy.
authors.forename: Luis
authors.initials: L
authors.lastname: Galietta
authors.affiliation: Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada.
authors.forename: David Y
authors.initials: DY
authors.lastname: Thomas
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.|Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Di Bernardo
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Luini
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D017510:Protein Folding; D059748:Proteolysis; D057165:Proteostasis Deficiencies / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction
chemical_list: C505032:CFTR protein, human; D004791:Enzyme Inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; Cystic fibrosis; computational biology; human biology; mechanism of action of drugs; medicine; proteostasis regulators; signalling networks; systems biology