Augmentation of CFTR maturation by S-nitrosoglutathione reductase

Am J Physiol Lung Cell Mol Physiol. 2016 Feb 1;310(3):L263-70. doi: 10.1152/ajplung.00269.2014. Epub 2015 Dec 4.


S-nitrosoglutathione (GSNO) reductase regulates novel endogenous S-nitrosothiol signaling pathways, and mice deficient in GSNO reductase are protected from airways hyperreactivity. S-nitrosothiols are present in the airway, and patients with cystic fibrosis (CF) tend to have low S-nitrosothiol levels that may be attributed to upregulation of GSNO reductase activity. The present study demonstrates that 1) GSNO reductase activity is increased in the cystic fibrosis bronchial epithelial (CFBE41o(-)) cells expressing mutant F508del-cystic fibrosis transmembrane regulator (CFTR) compared with the wild-type CFBE41o(-) cells, 2) GSNO reductase expression level is increased in the primary human bronchial epithelial cells expressing mutant F508del-CFTR compared with the wild-type cells, 3) GSNO reductase colocalizes with cochaperone Hsp70/Hsp90 organizing protein (Hop; Stip1) in human airway epithelial cells, 4) GSNO reductase knockdown with siRNA increases the expression and maturation of CFTR and decreases Stip1 expression in human airway epithelial cells, 5) increased levels of GSNO reductase cause a decrease in maturation of CFTR, and 6) a GSNO reductase inhibitor effectively reverses the effects of GSNO reductase on CFTR maturation. These studies provide a novel approach to define the subcellular location of the interactions between Stip1 and GSNO reductase and the role of S-nitrosothiols in these interactions.

Keywords: F508del-CFTR rescue; Hsp70/Hsp90 organizing protein; S-nitrosoglutathione reductase; S-nitrosothiols; cystic fibrosis transmembrane conductance regulator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Oxidoreductases / metabolism*
  • Aldehyde Oxidoreductases / pharmacology
  • Cell Line
  • Cell Membrane / metabolism
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Epithelial Cells / metabolism*
  • Humans
  • Signal Transduction / physiology


  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Aldehyde Oxidoreductases
  • formaldehyde dehydrogenase, glutathione-independent