F508del, the most frequent mutation in cystic fibrosis (CF), impairs the folding and stability of the CFTR chloride channel. This defect can be targeted with drugs named correctors. However, efficacy of correctors can be limited by cell processes that provoke the premature degradation of CFTR. This process involves the activity of ubiquitin ligases (UBLs), which are proteins that mark other proteins for degradation by attaching a tag named ubiquitin. There are also proteins named deubiquitinases (DUBs) that have the opposite function, protecting other proteins from degradation. Using gene silencing by siRNA transfection, the researchers have identified a panel of DUBs (USP13, USP15, UCHL1, BAP1, USP39, OTUD7B) and UBLs (HUWE1) that influence F508del-CFTR rescue by correctors. Experiments involving treatment of cells with compounds endowed with a complementary mechanism of action were also carried out. The results of this project demonstrate a protective effect of such treatments with improved rescue of CFTR function. Such findings could lead to the design of novel pharmacological treatments to maximize the correction of F508del and other CF mutations. Such treatments could involve activators of DUBs or inhibitors of UBLs to protect CFTR from degradation, thus enhancing the efficacy of correctors.
Pubblications
- Scudieri P et al, Ionocytes and CFTR chloride channel expression in normal and cystic fibrosis nasal and bronchial epithelial cells, Cells vol. 9,9 2090. 13 Sep. 2020
- Capurro V et al, Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment, International journal of molecular sciences vol. 22,10 5262. 17 May. 2021,
- Spanò V et al, Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein, Molecules vol. 26,5 1275. 26 Feb. 2021
- Venturini A, Borrelli A, Musante I et al, Comprehensive analysis of combinatorial pharmacological treatments to correct nonsense mutations in the CFTR Gene, International journal of molecular sciences vol. 22,21 11972. 4 Nov. 2021