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

Publication ,  Journal Article
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 ...
Published in: Proc Natl Acad Sci U S A
June 22, 2010

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.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 22, 2010

Volume

107

Issue

25

Start / End Page

11393 / 11398

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Signal Transduction
  • S-Nitrosoglutathione
  • Nitrogen
  • Mutation
  • Models, Biological
  • Humans
  • HSP90 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Genetic Therapy
 

Citation

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Marozkina, N. V., Yemen, S., Borowitz, M., Liu, L., Plapp, M., Sun, F., … Zaman, K. (2010). Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy. Proc Natl Acad Sci U S A, 107(25), 11393–11398. https://doi.org/10.1073/pnas.0909128107
Marozkina, Nadzeya V., Sean Yemen, Molly Borowitz, Lei Liu, Melissa Plapp, Fei Sun, Rafique Islam, et al. “Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy.Proc Natl Acad Sci U S A 107, no. 25 (June 22, 2010): 11393–98. https://doi.org/10.1073/pnas.0909128107.
Marozkina NV, Yemen S, Borowitz M, Liu L, Plapp M, Sun F, et al. Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11393–8.
Marozkina, Nadzeya V., et al. “Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy.Proc Natl Acad Sci U S A, vol. 107, no. 25, June 2010, pp. 11393–98. Pubmed, doi:10.1073/pnas.0909128107.
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. Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11393–11398.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 22, 2010

Volume

107

Issue

25

Start / End Page

11393 / 11398

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Signal Transduction
  • S-Nitrosoglutathione
  • Nitrogen
  • Mutation
  • Models, Biological
  • Humans
  • HSP90 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Genetic Therapy