HDAC3 as a molecular chaperone for shuttling phosphorylated TR2 to PML: a novel deacetylase activity-independent function of HDAC3.
HDAC3 as a molecular chaperone for shuttling phosphorylated TR2 to PML: a novel deacetylase activity-independent function of HDAC3.
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DOI：
10.1371/journal.pone.0004363
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Wei LN
中科院分区：
文献类型：
--
作者：
Gupta P;Ho PC;Ha SG;Lin YW;Wei LN
TR2是在早期胚胎中特异性表达的孤儿核受体（Wei and Hsu, 1994），也是干细胞中重要基因转录调控的转录因子，包括大门看门人Oct4 （Park et al. 2007）。众所周知，TR2可作为激活剂（Wei et al. 2000）或阻遏剂（Chinpaisal et al., 1998, Gupta et al. 2007）。由于缺乏特异性配体，触发其激活或抑制功能的机制几十年来一直令人困惑。最近，我们发现全反式维黄酸（atRA）触发细胞外信号调节激酶2 （ERK2）的激活，ERK2磷酸化TR2并刺激其向早幼粒细胞白血病（PML）核体的分配，从而将TR2的激活剂功能转化为抑制（Gupta et al. 2008; Park et al. 2007）。TR2向PML的募集是TR2从激活因子向抑制因子转化的关键步骤。然而，目前尚不清楚磷酸化的TR2如何被募集到PML中，这是将TR2从激活因子转化为抑制因子的重要步骤。在本研究中，我们使用体外和体内系统来解决将TR2招募到PML核体的问题。首先，我们确定组蛋白去乙酰化酶3 （HDAC3）是一个效应分子。已知HDAC3与TR2相互作用（Franco et al. 2001），这种相互作用通过atra刺激TR2在Thr-210位点的磷酸化而增强（Gupta et al. 2008）。其次，在本研究中，我们还发现HDAC3的载体功能独立于它的去乙酰化酶活性。第三，我们发现atRA的另一种新活性刺激HDAC3的核富集，与PML形成核复合物，这是ERK2无关的。这是第一个发现HDAC3的去乙酰酶独立功能的报告，它作为一种特定的载体分子，针对PML NBs特异性磷酸化蛋白。这也是第一个描述蛋白如何募集到PML核体的研究，这可以通过atRA以不依赖erk2的方式刺激。这些发现可以为潜在治疗方法的开发以及了解孤儿核受体活性如何在没有配体的情况下进行调节提供新的见解。
TR2 is an orphan nuclear receptor specifically expressed in early embryos (Wei and Hsu, 1994), and a transcription factor for transcriptional regulation of important genes in stem cells including the gate keeper Oct4 (Park et al. 2007). TR2 is known to function as an activator (Wei et al. 2000), or a repressor (Chinpaisal et al., 1998, Gupta et al. 2007). Due to the lack of specific ligands, mechanisms triggering its activator or repressor function have remained puzzling for decades. Recently, we found that all-trans retinoic acid (atRA) triggers the activation of extracellular-signal-regulated kinase 2 (ERK2), which phosphorylates TR2 and stimulates its partitioning to promyelocytic leukemia (PML) nuclear bodies, thereby converting the activator function of TR2 into repression (Gupta et al. 2008; Park et al. 2007). Recruitment of TR2 to PML is a crucial step in the conversion of TR2 from an activator to a repressor. However, it is unclear how phosphorylated TR2 is recruited to PML, an essential step in converting TR2 from an activator to a repressor. In the present study, we use both in vitro and in vivo systems to address the problem of recruiting TR2 to PML nuclear bodies. First, we identify histone deacetylase 3 (HDAC3) as an effector molecule. HDAC3 is known to interact with TR2 (Franco et al. 2001) and this interaction is enhanced by the atRA-stimulated phosphorylation of TR2 at Thr-210 (Gupta et al. 2008). Secondly, in this study, we also find that the carrier function of HDAC3 is independent of its deacetylase activity. Thirdly, we find another novel activity of atRA that stimulates nuclear enrichment of HDAC3 to form nuclear complex with PML, which is ERK2 independent. This is the first report identifying a deacetylase-independent function for HDAC3, which serves as a specific carrier molecule that targets a specifically phosphorylated protein to PML NBs. This is also the first study delineating how protein recruitment to PML nuclear bodies occurs, which can be stimulated by atRA in an ERK2-independent manner. These findings could provide new insights into the development of potential therapeutics and in understanding how orphan nuclear receptor activities can be regulated without ligands.
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