S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation

Endogenous S-nitrosoglutathione (GSNO) is known to increase the expression of certain proteins at concentrations present in the normal human airway. W e hypothesized that GSNO would increase expression and maturation of the cy stic fibrosis transmembrane conductance regulator (CFTR). Cells expressing Delta F508 and wild type CFTR were exposed to GBNO and analyzed for express ion and maturation by Western blot analysis. Physiologically relevant conce ntrations of GSNO resulted in dose- and time-dependent increases in express ion. The GSNO-induced increases were eliminated by cycloheximide, suggestin g a posttranscriptional effect. Unlike proteasome inhibitors, GSNO resulted in an increase CFTR maturation. The GSNO effect could be reversed by dithi othreitol and inhibited by acivicin, a gamma glutamyl transpeptidase inhibi tor. These observations suggest that GSNO leads to maturation of mutated De lta F508 CFTR, a process associated with restoration of CFTR function. Beca use endogenous levels of GSNO are low in the cystic fibrosis (CF) airway, t hese results raise the possibility that GSNO replacement therapy could be a n effective treatment for CF. (C) 2001 Academic Press.