Augmentation of CFTR maturation by S-nitrosoglutathione reductase

作者：Zaman Khalequz; Sawczak Victoria; Zaidi Atiya; Butler Maya; Bennett Deric; Getsy Paulina; Zeinomar Maryam; Greenberg Zivi; Forbes Michael; Rehman Shagufta; Jyothikumar Vinod; DeRonde Kim; Sattar Abdus; Smith Laura; Corey Deborah; Straub Adam; Sun Fei; Palmer Lisa; Periasamy Ammasi; Randell Scott; Kelley Thomas J; Lewis Stephen J; Gaston Benjamin^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2016, 310(3): L263-L270.

DOI：10.1152/ajplung.00269.2014

• cystic fibrosis transmembrane conductance regulator
• S-nitrosothiols
• F508del-CFTR rescue
• S-nitrosoglutathione reductase
• Hsp70/Hsp90 organizing protein

Snitrosoglutathione (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.

• 出版日期2016-2-1