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

Nadzeya V. Marozkina, Sean Yemen, Molly Borowitz, Lei Liu, Melissa Plapp, Fei Sun, Rafique Islam, Petra Erdmann-Gilmore, R. Reid Townsend, Cheryl F. Lichti, Sneha Mantri, Phillip W. Clapp, Scott H. Randell, Benjamin Gaston, Khalequz Zaman

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product ΔF508 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 ΔF508 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 ΔF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on ΔF508 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 ΔF508 CFTR trafficking by inhibiting Hop expression, and that combination therapies - using differing mechanisms of action - may have additive benefits in treating CF.

Original languageEnglish (US)
Pages (from-to)11393-11398
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number25
DOIs
StatePublished - Jun 22 2010

Keywords

  • Cystic fibrosis transmembrane conductance regulator
  • S-nitrosoglutathione corrector
  • Treatment

ASJC Scopus subject areas

  • General

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    Marozkina, N. V., Yemen, S., Borowitz, M., Liu, L., Plapp, M., Sun, F., Islam, R., Erdmann-Gilmore, P., Townsend, R. R., Lichti, C. F., Mantri, S., Clapp, P. W., Randell, S. H., Gaston, B., & Zaman, K. (2010). Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy. Proceedings of the National Academy of Sciences of the United States of America, 107(25), 11393-11398. https://doi.org/10.1073/pnas.0909128107