Is it go or NO go for S-nitrosylation modification-based therapies of cystic fibrosis transmembrane regulator trafficking?
Nitric-oxide synthases (NOS) are abundant in the respiratory epithelium and generate the NO radical, which can activate guanylate cyclase, react with superoxide, or modify proteins by S-nitrosylation (SNO) of Cys thiols. There is increasing appreciation that SNO modification is analogous to phosphorylation, because both signaling mechanisms modulate a wide range of cellular functions. Zaman et al. (p. 1435) in this issue report on the capability of S-nitrosoglutathione (GSNO) to increase the expression, trafficking, and function of mutant and wild-type cystic fibrosis transmembrane regulator (CFTR). The CFTR is a cAMP-regulated chloride channel that functions to regulate salt and water content in glands and ducts of secretory epithelia. GSNO is a low molecular weight SNO (S-nitrosothiol) formed during oxidation of NO. The authors use GSNO as a lead compound to restore mutant CFTR function. Earlier contradictory reports that GSNO decreased CFTR function by oxidative modification (glutathionylation) may now be explained by high concentrations of GSNO associated with decreased CFTR transcription and disruption of CFTR function. Zaman et al. show that at physiologic concentrations, GSNO and the constitutively active S-nitroso-glutathione diethyl ester stimulate CFTR transcription through SP1 and SP3 and promote normal trafficking. The mechanism behind rescue from the degradative pathway relies on increasing the expression of cysteine string proteins and SNO modification of chaperones involved in mediating CFTR transit through the endoplasmic reticulum and Golgi apparatus.
Zeitlin
Pamela L
PL
Department of Pediatrics, Eudowood Division of Pediatric Respiratory Sciences, The Johns Hopkins School of Medicine, Park 316, 600 N. Wolfe St., Baltimore, MD 21287, USA. pzeitlin@jhmi.edu
D003550:Cystic Fibrosis / Q000378:metabolism* / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D014644:Genetic Variation; D050956:HSP40 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D026422:S-Nitrosoglutathione / Q000494:pharmacology*
D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D019001:Nitric Oxide Synthase