title: Augmentation of CFTR maturation by S-nitrosoglutathione reductase.
abstract: 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.
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Khalequz
authors.identifier: http://orcid.org/0000-0001-9987-0388
authors.initials: K
authors.lastname: Zaman
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Victoria
authors.initials: V
authors.lastname: Sawczak
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Atiya
authors.initials: A
authors.lastname: Zaidi
authors.affiliation: Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Maya
authors.initials: M
authors.lastname: Butler
authors.affiliation: Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Deric
authors.initials: D
authors.lastname: Bennett
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Paulina
authors.initials: P
authors.lastname: Getsy
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Maryam
authors.initials: M
authors.lastname: Zeinomar
authors.affiliation: Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Zivi
authors.initials: Z
authors.lastname: Greenberg
authors.affiliation: Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Michael
authors.initials: M
authors.lastname: Forbes
authors.affiliation: W. M. Keck Center for Cellular Imaging, Department of Biology, University of Virginia, Charlottesville, Virginiga;
authors.forename: Shagufta
authors.initials: S
authors.lastname: Rehman
authors.affiliation: W. M. Keck Center for Cellular Imaging, Department of Biology, University of Virginia, Charlottesville, Virginiga;
authors.forename: Vinod
authors.initials: V
authors.lastname: Jyothikumar
authors.affiliation: Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Kim
authors.initials: K
authors.lastname: DeRonde
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Abdus
authors.initials: A
authors.lastname: Sattar
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Laura
authors.initials: L
authors.lastname: Smith
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Deborah
authors.initials: D
authors.lastname: Corey
authors.affiliation: Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Adam
authors.initials: A
authors.lastname: Straub
authors.affiliation: Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan;
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Pediatric Respiratory Medicine, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia;
authors.forename: Lisa
authors.initials: L
authors.lastname: Palmer
authors.affiliation: W. M. Keck Center for Cellular Imaging, Department of Biology, University of Virginia, Charlottesville, Virginiga;
authors.forename: Ammasi
authors.initials: A
authors.lastname: Periasamy
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;
authors.forename: Scott
authors.initials: S
authors.lastname: Randell
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kelley
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio;
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lewis
authors.affiliation: Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio; Pediatric Pulmonology Division, Rainbow Babies and Children's Hospital, Cleveland, Ohio bmg46@case.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000445:Aldehyde Oxidoreductases; C087006:formaldehyde dehydrogenase, glutathione-independent
keywords: F508del-CFTR rescue; Hsp70/Hsp90 organizing protein; S-nitrosoglutathione reductase; S-nitrosothiols; cystic fibrosis transmembrane conductance regulator