Department of Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
J Biol Chem. 2012 Apr 6;287(15):12111-20. doi: 10.1074/jbc.M111.327023. Epub 2012 Feb 15.
An important step in transcriptional regulation by corepressors N-CoR and SMRT is the formation of a stable and active histone deacetylase 3 (HDAC3)-containing complex. Although N-CoR and SMRT are thought to bind HDAC3 competitively, multiple studies have shown that they do not interfere with the function of each other. How this functional independence is sustained under the competitive interaction is unclear. Here, we show that the coupling of corepressor expression with HDAC3 degradation allows cells to maintain a stable level of uncomplexed HDAC3, thereby preventing mutual interference in the assembly of N-CoR and SMRT complexes. The free uncomplexed HDAC3 is highly unstable. Unexpectedly, the rate of HDAC3 degradation is inversely correlated with the expression level of corepressors. Our results indicate that reducing one corepressor accelerates HDAC3 clearance, thus preventing an increase in complex formation between HDAC3 and the other corepressor. In addition, this study also indicates that the formation of a stable and active HDAC3-corepressor complex is a stepwise process in which the C terminus of HDAC3 plays a critical role at late steps of the assembly process.
核受体共抑制因子 N-CoR 和 SMRT 进行转录调控的一个重要步骤是形成一个稳定且有活性的组蛋白去乙酰化酶 3（HDAC3）复合物。尽管 N-CoR 和 SMRT 被认为是竞争性地结合 HDAC3，但多项研究表明它们不会相互干扰对方的功能。在竞争相互作用下，这种功能独立性是如何维持的尚不清楚。在这里，我们表明，共抑制因子表达与 HDAC3 降解的偶联允许细胞维持未复合 HDAC3 的稳定水平，从而防止 N-CoR 和 SMRT 复合物组装过程中的相互干扰。游离的未复合的 HDAC3 极不稳定。出乎意料的是，HDAC3 降解的速度与共抑制因子的表达水平呈反比。我们的结果表明，降低一种共抑制因子会加速 HDAC3 的清除，从而防止 HDAC3 与另一种共抑制因子之间复合物形成的增加。此外，这项研究还表明，形成稳定且有活性的 HDAC3-共抑制因子复合物是一个逐步的过程，其中 HDAC3 的 C 末端在组装过程的后期步骤中起着关键作用。
