Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis

Darren M. Hutt, David Herman, Ana P.C. Rodrigues, Sabrina Noel, Joseph M. Pilewski, Jeanne Matteson, Ben Hoch, Wendy Kellner, Jeffery W. Kelly, Andre Schmidt, Philip J. Thomas, Yoshihiro Matsumura, William R. Skach, Martina Gentzsch, John R. Riordan, Eric J. Sorscher, Tsukasa Okiyoneda, John R. Yates, Gergely L. Lukacs, Raymond A. FrizzellGerard Manning, Joel M. Gottesfeld, William E. Balch

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

Chemical modulation of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACi) is an increasingly important approach for modifying the etiology of human disease. Loss-of-function diseases arise as a consequence of protein misfolding and degradation, which lead to system failures. The Î "F508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) results in the absence of the cell surface chloride channel and a loss of airway hydration, leading to the premature lung failure and reduced lifespan responsible for cystic fibrosis. We now show that the HDACi suberoylanilide hydroxamic acid (SAHA) restores surface channel activity in human primary airway epithelia to levels that are 28% of those of wild-type CFTR. Biological silencing of all known class I and II HDACs reveals that HDAC7 plays a central role in restoration of δF508 function. We suggest that the tunable capacity of HDACs can be manipulated by chemical biology to counter the onset of cystic fibrosis and other human misfolding disorders.

Original languageEnglish (US)
Pages (from-to)25-33
Number of pages9
JournalNature Chemical Biology
Volume6
Issue number1
DOIs
StatePublished - Jan 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis'. Together they form a unique fingerprint.

  • Cite this

    Hutt, D. M., Herman, D., Rodrigues, A. P. C., Noel, S., Pilewski, J. M., Matteson, J., Hoch, B., Kellner, W., Kelly, J. W., Schmidt, A., Thomas, P. J., Matsumura, Y., Skach, W. R., Gentzsch, M., Riordan, J. R., Sorscher, E. J., Okiyoneda, T., Yates, J. R., Lukacs, G. L., ... Balch, W. E. (2010). Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nature Chemical Biology, 6(1), 25-33. https://doi.org/10.1038/nchembio.275