Unravelling druggable signalling networks that control F508del-CFTR proteostasis.

Autor: Hegde RN; Institute of Protein Biochemistry, National Research Council, Naples, Italy.; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Parashuraman S; Institute of Protein Biochemistry, National Research Council, Naples, Italy.; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Iorio F; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Ciciriello F; 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., Capuani F; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Carissimo A; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Carrella D; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Belcastro V; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Subramanian A; Institute of Protein Biochemistry, National Research Council, Naples, Italy., Bounti L; Institute of Protein Biochemistry, National Research Council, Naples, Italy., Persico M; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy., Carlile G; Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada., Galietta L; U.O.C. Genetica Medica, Institute of Giannina Gaslini, Genova, Italy., Thomas DY; Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Canada., Di Bernardo D; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.; Department of Electrical Engineering and Information Technology, University of Naples Federico II, Naples, Italy., Luini A; 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.
Jazyk: angličtina
Zdroj: ELife [Elife] 2015 Dec 23; Vol. 4. Date of Electronic Publication: 2015 Dec 23.
DOI: 10.7554/eLife.10365
Abstrakt: 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.
Databáze: MEDLINE
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