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Mol Cell Pediatr. 2016 Dec;3(1):13. doi: 10.1186/s40348-016-0040-z. Epub 2016 Mar 14.

Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis.

Esposito S1, Tosco A2, Villella VR1, Raia V3, Kroemer G4,5,6,7,8,9,10, Maiuri L11,12.

Author information

1
European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, 20132, Italy.
2
Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples, 80131, Italy.
3
Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, Federico II University, Naples, 80131, Italy. raia@unina.it.
4
Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. kroemer@orange.fr.
5
Cell Biology and Metabolomics Platforms, GustaveRoussy Comprehensive Cancer Center, Villejuif, France. kroemer@orange.fr.
6
INSERM, U1138, Paris, France. kroemer@orange.fr.
7
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. kroemer@orange.fr.
8
Université Pierre et Marie Curie, Paris, France. kroemer@orange.fr.
9
Pôle de Biologie, HôpitalEuropéen Georges Pompidou, AP-HP, Paris, France. kroemer@orange.fr.
10
Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden. kroemer@orange.fr.
11
European Institute for Research in Cystic Fibrosis, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, 20132, Italy. luigi.maiuri@gmail.com.
12
SCDU of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara, 28100, Italy. luigi.maiuri@gmail.com.

Abstract

Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

KEYWORDS:

Autophagy; CFTR; CFTR-repairing therapy; Cystic fibrosis; Proteostasis

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