Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis.
Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis.
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DOI：
10.1038/nchembio.275
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发表时间：
2010-01
影响因子：
14.8
通讯作者：
Balch WE
中科院分区：
文献类型：
--
作者：
Hutt DM;Herman D;Rodrigues AP;Noel S;Pilewski JM;Matteson J;Hoch B;Kellner W;Kelly JW;Schmidt A;Thomas PJ;Matsumura Y;Skach WR;Gentzsch M;Riordan JR;Sorscher EJ;Okiyoneda T;Yates JR 3rd;Lukacs GL;Frizzell RA;Manning G;Gottesfeld JM;Balch WE
通过组蛋白去乙酰化酶抑制剂（HDACi）化学调节组蛋白去乙酰化酶（HDAC）活性是改变人类疾病病因的日益重要的方法。功能丧失性疾病是由于蛋白质错误折叠和降解导致系统故障而产生的。囊性纤维化跨膜传导调节因子（CFTR）中的ΔF508突变导致细胞表面氯离子通道的缺失和气道水合作用的丧失，从而导致过早的肺衰竭和导致囊性纤维化（CF）的寿命缩短。我们现在显示HDACi辛二酰苯胺异羟肟酸（SAHA）将人原代气道上皮中的表面通道活性恢复至野生型CFTR的28%的水平。所有已知的I类和II类HDAC的生物学沉默揭示了HDAC 7在ΔF508功能的恢复中起核心作用。我们认为HDAC的可调能力可以通过化学生物学来操纵，以对抗CF和其他人类错误折叠疾病的发作。
Chemical modulation of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACi) is an increasingly important approach to modify the etiology of human disease. Loss-of-function diseases arise as a consequence of protein misfolding and degradation leading to system failures. The ΔF508 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 premature lung failure and reduced lifespan responsible for cystic fibrosis (CF). 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 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 CF and other human misfolding disorders.
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影响因子：
5.5
作者：
Bebok, Z;Collawn, JF;Clancy, JP
通讯作者：
Clancy, JP
影响因子：
11.1
作者：
Boucher, R. C.
通讯作者：
Boucher, R. C.
影响因子：
64.5
作者：
Chang, Shurong;Young, Bryan D.;Olson, Eric N.
通讯作者：
Olson, Eric N.
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
Hutt, Darren M.;Powers, Evan T.;Balch, William E.
通讯作者：
Balch, William E.