Mdm2 is required for HDAC3 monoubiquitination and stability
Mdm2 is required for HDAC3 monoubiquitination and stability
复制标题
DOI：
10.1016/j.bbrc.2019.07.052
复制
发表时间：
2019-09-17
影响因子：
3.1
通讯作者：
Jung, Jin Hyuk
中科院分区：
文献类型：
--
作者：
Choi, Yeong Min;An, Sungkwan;Jung, Jin Hyuk
HDAC3是一类组蛋白去乙酰化酶，通过组蛋白修饰调控表观遗传景观。HDAC3也与非组蛋白相互作用，包括p53去乙酰化。此外，HDAC3作为转录抑制因子，与NCorl/SMRT复合物相互作用。虽然HDAC3在细胞内稳态中起关键作用，但HDAC3的调控机制尚不清楚。在这里，我们报道了HDAC3的单泛素化和Mdm2稳定的新调控机制。在不同细胞系中，HDAC3水平因Mdm2异位表达而升高，因Mdm2消融而降低。我们发现Mdm2直接与HDAC3相互作用，诱导HDAC3蛋白水平而不改变mRNA水平。异位表达野生型而非RING突变型Mdm2增加了HDAC3的单泛素化。此外，MdmX有利于mdm2介导的HDAC3调控。消融Mdm2和Mdm2/MdmX可减少细胞迁移，同时HDAC3水平降低。这些数据提供了Mdm2正调控HDAC3单泛素化和稳定性的证据。(C) 2019 Elsevier Inc.版权所有。
HDAC3, one of the class I histone deacetylase modulates epigenetic landscape through histone modification. HDAC3 also interacts with non-histone proteins including p53 for deacetylation. Moreover, HDAC3 serves as a transcriptional repressor, interacting with NCorl/SMRT complex. Although HDAC3 plays a critical role for cellular homeostasis, regulatory mechanism of HDAC3 have been poorly understood. Here we report a novel regulatory mechanism of HDAC3 about its monoubiquitination and stabilization by Mdm2. HDAC3 levels were increased by ectopic expression of Mdm2 and decreased by Mdm2 ablation in various cell lines. We found that Mdm2 directly interacts with HDAC3 and induces HDAC3 protein levels without alteration of mRNA levels. Ectopic expression of wild type but not RING mutant of Mdm2 increased HDAC3 monoubiquitination. In addition, MdmX is beneficial for mdm2-mediated HDAC3 regulation. Ablation of Mdm2 and Mdm2/MdmX decreased cell migration along with the decrease of HDAC3 levels. These data provide an evidence that Mdm2 positively regulates HDAC3 monoubiquitination and stability. (C) 2019 Elsevier Inc. All rights reserved.