S-Nitrosothiol Breakdown by Airway Epithelial Cells

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): S-Nitrosothiols are endogenous adducts of nitric oxide and cysteine thiols. Increasingly, it is appreciated that S-nitrosylation reactions may result in post-translational protein modifications. These modifications have been associated with cyclic GMP-independent bioactivities that may be regulated to physiological advantage. For example, proteins may be modified by transnitrosation reactions with S-nitrosylated peptides such as S-nitrosoglutathione, concentrations of which appear to be enzymatically regulated. Indeed, several enzymes are now appreciated to regulate the catabolism of S-nitrosoglutathione, including glutathione-dependent formaldehyde dehydrogenase and gamma-glutamyl transpeptidase. S-nitrosothiol biochemistry may be involved in the regulation of a broad spectrum of bioactivities in the airway, including ion channel conductivity, inflammatory cell apoptosis, and airway smooth muscle relaxation. Of note, we have recently observed that S-nitrosoglutathione increases the expression and maturation of the most common mutant form of cystic fibrosis transmembrane regulatory protein (CFTR), deltaF508. Levels of S-nitrosothiols appear to be low in the airways of patients with both cystic fibrosis and with asthma, in part because of increased activity of S-nitrosoglutathione catabolic enzymes. Indeed, if it was not for accelerated S-nitrosoglutathione catabolism, S-nitrosoglutathione replacement therapy could be envisioned as a novel therapy for both cystic fibrosis and asthma. In this project, we plan to 1) characterize the regulation of S-nitrosothiol catabolism in the cystic fibrosis and asthmatic airway epithelium; 2) define the mechanism by which S-nitrosoglutathione and other S-nitrosothiols may increase the maturation of kF508 CFTR; and 3) evaluate mechanisms by which S-nitrosoglutathione catabolism might be circumvented to achieve salutary bioactivities in the airways, including increased CFTR maturation. We anticipate that this project will provide new tools for understanding the cell biology of cystic fibrosis and asthma, and that it may lead to the development of new therapies for both diseases.