TY - JOUR
T1 - Unravelling druggable signalling networks that control F508del-CFTR proteostasis
AU - Hegde, Ramanath Narayana
AU - Parashuraman, Seetharaman
AU - Iorio, Francesco
AU - Ciciriello, Fabiana
AU - Capuani, Fabrizio
AU - Carissimo, Annamaria
AU - Carrella, Diego
AU - Belcastro, Vincenzo
AU - Subramanian, Advait
AU - Bounti, Laura
AU - Persico, Maria
AU - Carlile, Graeme
AU - Galietta, Luis
AU - Thomas, David Y.
AU - di Bernardo, Diego
AU - Luini, Alberto
PY - 2015/12/23
Y1 - 2015/12/23
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.10365
DO - 10.7554/eLife.10365
M3 - Article
AN - SCOPUS:84956877149
VL - 4
JO - eLife
JF - eLife
SN - 2050-084X
IS - DECEMBER2015
M1 - e10365
ER -