In cortical neurons HDAC3 activity suppresses RD4-dependent SMRT export.
In cortical neurons HDAC3 activity suppresses RD4-dependent SMRT export.
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DOI：
10.1371/journal.pone.0021056
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
Soriano FX;Hardingham GE
转录共抑制因子SMRT控制几种转录因子的神经元反应性，可以调节神经保护和神经发生途径。SMRT是一种多结构域蛋白，可与HDAC3复合物，并能与hdac1、4、5和7相互作用。我们之前的研究表明，在大鼠皮质神经元中，SMRT的核定位需要组蛋白去乙酰化酶的活性：用曲古斯汀A （TSA）抑制I/II类hdac会导致SMRT重新分布到细胞质中，并增强SMRT被抑制的核受体的激活。在这里，我们试图确定SMRT的HDAC和区域，在正常情况下负责将其锚定在细胞核中，并在HDAC抑制后介导核输出。我们发现，在大鼠皮层神经元中，SMRT输出可以通过i类HDAC抑制剂丙戊酸盐和hdac2 /3选择性抑制剂apicidin治疗，以及HDAC3敲低触发，这表明HDAC3活性是维持核内SMRT所必需的。HDAC3与SMRT的去乙酰化激活域（DAD）的相互作用对于HDAC3去乙酰化酶功能的激活是重要的。与HDAC3活性在促进SMRT核定位中的作用一致，我们发现通过缺失或点突变使SMRT的DAD失活可触发SMRT向细胞质的部分重新分配。我们还研究了SMRT的其他区域是否参与介导HDAC抑制后的核输出。TSA和丙戊酸盐诱导的SMRT输出被其抑制结构域4 （RD4）的缺失严重损害。此外，含有RD4区域的SMRT区域的过表达抑制了tsa诱导的全长SMRT的输出。总的来说，这些数据支持一个模型，即SMRT的RD4区域可以招募能够介导SMRT核输出的因子，但其功能和/或招募受到HDAC3活性的抑制。此外，他们强调了一个事实，即HDAC抑制剂可以引起共抑制因子复合物的重组和重新分配。
The transcriptional corepressor SMRT controls neuronal responsiveness of several transcription factors and can regulate neuroprotective and neurogenic pathways. SMRT is a multi-domain protein that complexes with HDAC3 as well as being capable of interactions with HDACs 1, 4, 5 and 7. We previously showed that in rat cortical neurons, nuclear localisation of SMRT requires histone deacetylase activity: Inhibition of class I/II HDACs by treatment with trichostatin A (TSA) causes redistribution of SMRT to the cytoplasm, and potentiates the activation of SMRT-repressed nuclear receptors. Here we have sought to identify the HDAC(s) and region(s) of SMRT responsible for anchoring it in the nucleus under normal circumstances and for mediating nuclear export following HDAC inhibition. We show that in rat cortical neurons SMRT export can be triggered by treatment with the class I-preferring HDAC inhibitor valproate and the HDAC2/3-selective inhibitor apicidin, and by HDAC3 knockdown, implicating HDAC3 activity as being required to maintain SMRT in the nucleus. HDAC3 interaction with SMRT's deacetylation activation domain (DAD) is known to be important for activation of HDAC3 deacetylase function. Consistent with a role for HDAC3 activity in promoting SMRT nuclear localization, we found that inactivation of SMRT's DAD by deletion or point mutation triggered partial redistribution of SMRT to the cytoplasm. We also investigated whether other regions of SMRT were involved in mediating nuclear export following HDAC inhibition. TSA- and valproate-induced SMRT export was strongly impaired by deletion of its repression domain-4 (RD4). Furthermore, over-expression of a region of SMRT containing the RD4 region suppressed TSA-induced export of full-length SMRT. Collectively these data support a model whereby SMRT's RD4 region can recruit factors capable of mediating nuclear export of SMRT, but whose function and/or recruitment is suppressed by HDAC3 activity. Furthermore, they underline the fact that HDAC inhibitors can cause reorganization and redistribution of corepressor complexes.
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