Received for publication February 6, 2006.
Revised July 11, 2006.
Accepted for publication July 11, 2006.

A Novel Class Of Compounds That Increase CFTR Expression And Maturation In Epithelial Cells

Abstract

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 appears 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 µM concentrations, increase F508 and wild-type CFTR expression and maturation; 2) NO itself (at these concentrations) and 8-bromo-cyclic GMP are minimally active on CFTR; 3) a novel agent, S-nitroso-glutathione diethyl ester, bypasses the need for GSNO bioactivation by -glutamyl transpeptidase (GGT) 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; and 6) proteins relevant to CFTR trafficking are SNO-modified, and SNO-proteins traffic through the endoplasmic reticulum (ER) and Golgi following 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 classical NO radical/cyclic GMP pathway to increase CFTR expression and maturation. They also suggest 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.

Key words: Regulation - post-transcriptional, Glutathione

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