SYVN1, NEDD8, and FBXO2 Proteins Regulate ?F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation.

ABSTRACT: We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (?F508/?F508) airway epithelia partially restored ?F508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl^- conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ?F508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ?F508-CFTR-mediated Cl^- transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ?F508-CFTR-mediated Cl^- conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ?F508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ?F508-CFTR ubiquitination.

SUBMITTER: Ramachandran S 

PROVIDER: S-EPMC5207249 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature