Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis.
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 DeltaF508 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 DeltaF508 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.
Hutt
Darren M
DM
Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA.
Herman
David
D
Rodrigues
Ana P C
AP
Noel
Sabrina
S
Pilewski
Joseph M
JM
Matteson
Jeanne
J
Hoch
Ben
B
Kellner
Wendy
W
Kelly
Jeffery W
JW
Schmidt
Andre
A
Thomas
Philip J
PJ
Matsumura
Yoshihiro
Y
Skach
William R
WR
Gentzsch
Martina
M
Riordan
John R
JR
Sorscher
Eric J
EJ
Okiyoneda
Tsukasa
T
Yates
John R
JR
Lukacs
Gergely L
GL
Frizzell
Raymond A
RA
Manning
Gerard
G
Gottesfeld
Joel M
JM
Balch
William E
WE
D000818:Animals; D001980:Bronchi / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000378:metabolism; D000077337:Vorinostat
C505032:CFTR protein, human; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000077337:Vorinostat; C543273:HDAC7 protein, human; D006655:Histone Deacetylases