Fischle W, Verdin E, Greene W C
Gladstone Institute of Virology and Immunology, Department of Medicine, University of California, San Francisco, CA 94141, USA.
Science. 2001 Aug 31;293(5535):1653-7. doi: 10.1126/science.1062374.
The nuclear expression and action of the nuclear factor kappa B (NF-kappaB) transcription factor requires signal-coupled phosphorylation and degradation of the IkappaB inhibitors, which normally bind and sequester this pleiotropically active factor in the cytoplasm. The subsequent molecular events that regulate the termination of nuclear NF-kappaB action remain poorly defined, although the activation of de novo IkappaBalpha gene expression by NF-kappaB likely plays a key role. Our studies now demonstrate that the RelA subunit of NF-kappaB is subject to inducible acetylation and that acetylated forms of RelA interact weakly, if at all, with IkappaBalpha. Acetylated RelA is subsequently deacetylated through a specific interaction with histone deacetylase 3 (HDAC3). This deacetylation reaction promotes effective binding to IkappaBalpha and leads in turn to IkappaBalpha-dependent nuclear export of the complex through a chromosomal region maintenance-1 (CRM-1)-dependent pathway. Deacetylation of RelA by HDAC3 thus acts as an intranuclear molecular switch that both controls the duration of the NF-kappaB transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-kappaB-IkappaBalpha complexes.
核因子κB（NF-κB）转录因子的核表达及作用需要信号偶联的IκB抑制蛋白磷酸化及降解，IκB抑制蛋白通常在细胞质中结合并隔离这种具有多效活性的因子。尽管NF-κB对IκBα基因从头表达的激活可能起关键作用，但调节核内NF-κB作用终止的后续分子事件仍不清楚。我们现在的研究表明，NF-κB的RelA亚基可被诱导乙酰化，且乙酰化形式的RelA与IκBα的相互作用很弱（如果有相互作用的话）。乙酰化的RelA随后通过与组蛋白去乙酰化酶3（HDAC3）的特异性相互作用而发生去乙酰化。这种去乙酰化反应促进了与IκBα的有效结合，进而通过依赖染色体区域维持蛋白1（CRM-1）的途径导致该复合物依赖IκBα的核输出。因此，HDAC3介导的RelA去乙酰化作为一种核内分子开关，既控制NF-κB转录反应的持续时间，又有助于补充耗尽的细胞质中潜在的NF-κB-IκBα复合物池。
