Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy.

Published

Journal Article

The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product DeltaF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in DeltaF508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of DeltaF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on DeltaF508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects DeltaF508 CFTR trafficking by inhibiting Hop expression, and that combination therapies--using differing mechanisms of action--may have additive benefits in treating CF.

Full Text

Duke Authors

Cited Authors

  • Marozkina, NV; Yemen, S; Borowitz, M; Liu, L; Plapp, M; Sun, F; Islam, R; Erdmann-Gilmore, P; Townsend, RR; Lichti, CF; Mantri, S; Clapp, PW; Randell, SH; Gaston, B; Zaman, K

Published Date

  • June 22, 2010

Published In

Volume / Issue

  • 107 / 25

Start / End Page

  • 11393 - 11398

PubMed ID

  • 20534503

Pubmed Central ID

  • 20534503

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.0909128107

Language

  • eng

Conference Location

  • United States