F508del, the most frequent mutation in cystic fibrosis (CF), impairs the maturation and trafficking of CFTR protein. Despite the treatment with pharmacological correctors, a large fraction of F508del-CFTR does not reach the plasma membrane and is degraded by cell quality control mechanisms. Researchers proposal will focus on the identification of deubiquitinases (DUBs) and ubiquitin ligases (UBLs) that control mutant CFTR degradation. They aim to identify DUBs that protect F508del-CFTR from degradation using a gene silencing approach, i.e. a library of siRNAs against all known DUBs. The screening and subsequent validation with functional/biochemical assays will reveal which DUBs affect F508del-CFTR rescue. Since DUBs and specific UBLs often form pairs of enzymes with opposing activity, the identified DUBs will be a way to select, among the hundreds of UBLs, which ones are most important for F508del-CFTR degradation. Such information may pave the way for the development of pharmacological strategies (aiming at the upregulation of a DUB or the inhibition of a UBL) to maximize mutant CFTR rescue.