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S-Nitrosylating Agents: A Novel Class of Compounds That Increase Cystic Fibrosis Transmembrane Conductance Regulator Expression and Maturation in Epithelial Cells

Department of Pediatrics, Division of Respiratory Medicine, University of Virginia Health System, Charlottesville, Virginia (K.Z., S.C., J.D., E.M.H., E.L., E.P., L.A.P., A.D., B.G.); Division of Biostatistics and Epidemiology, Department of Public Health Sciences (L.L.) and Department of Internal Medicine, Pulmonary Division, University of Virginia School of Medicine, Charlottesville, Virginia (G.V.); Departments of Chemistry (M.Z.) and Urology (M.R.), University of Virginia, Charlottesville, Virginia; and Departments of Medicine and Biochemistry, Duke University School of Medicine, Durham, North Carolina (J.S.S.)

The endogenous bronchodilator, S-nitrosoglutathione (GSNO), increases expression, maturation, and function of both the wild-type and the F508 mutant of the cystic fibrosis transmembrane conductance regulatory protein (CFTR). Though transcriptional mechanisms of action have been identified, GSNO seems also to have post-transcriptional effects on CFTR maturation. Here, we report that 1) GSNO is only one of a class of S-nitrosylating agents that, at low micromolar concentrations, increase F508 and wild-type CFTR expression and maturation; 2) NO itself (at these concentrations) and 8-bromocyclic GMP are minimally active on CFTR; 3) a novel agent, S-nitrosoglutathione diethyl ester, bypasses the need for GSNO bioactivation by -glutamyl transpeptidase to increase CFTR maturation; 4) surprisingly, expression—but not S-nitrosylation—of cysteine string proteins (Csp) 1 and 2 is increased by GSNO; 5) the effect of GSNO to increase full maturation of wild-type CFTR is inhibited by Csp silencing (si)RNA; 6) proteins relevant to CFTR trafficking are SNO-modified, and SNO proteins traffic through the endoplasmic reticulum (ER) and Golgi after GSNO exposure; and 7) GSNO alters the interactions of F508 CFTR with Csp and Hsc70 in the ER and Golgi. These data suggest that GSNO is one of a class of S-nitrosylating agents that act independently of the classic NO radical/cyclic GMP pathway to increase CFTR expression and maturation. They also suggest that the effect of GSNO is dependent on Csp and on intracellular SNO trafficking. We speculate that these data will be of relevance to the development of NO donor-based therapies for CF.

Address correspondence to: Dr. Benjamin Gaston, Ivy Foundation Professor of Pediatrics, University of Virginia Health System, Pediatric Respiratory Medicine, Box 800386, Charlottesville, VA 22908. E-mail: bmg3g{at}virginia.edu

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Is It Go or NO Go for S-Nitrosylation Modification-Based Therapies of Cystic Fibrosis Transmembrane Regulator Trafficking?

Pamela L. Zeitlin
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				D. J. Carver, B. Gaston, K. deRonde, and L. A. Palmer Akt-Mediated Activation of HIF-1 in Pulmonary Vascular Endothelial Cells by S-Nitrosoglutathione Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 255 - 263. [Abstract] [Full Text] [PDF]

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