The Ubiquitin Carboxyl Hydrolase BAP1 Forms a Ternary Complex with YY1 and HCF-1 and Is a Critical Regulator of Gene Expression
The Ubiquitin Carboxyl Hydrolase BAP1 Forms a Ternary Complex with YY1 and HCF-1 and Is a Critical Regulator of Gene Expression
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DOI：
10.1128/mcb.00396-10
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发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Affar, El Bachir
中科院分区：
文献类型：
--
作者：
Yu, Helen;Mashtalir, Nazar;Affar, El Bachir
候选肿瘤抑制因子BAP1是一种去泛素化酶（DUB），参与细胞增殖的调节，尽管控制其功能的分子机制仍不明确。BAP1最近被证明与转录调节因子宿主细胞因子1 （HCF-1）相互作用并去泛素化。在这里，我们发现BAP1组装了包含许多转录因子和辅助因子的多蛋白复合物，包括HCF-1和转录因子阴阳1 （YY1）。BAP1通过其coil -coil基序直接与YY1的锌指相互作用。此外，HCF-1与YY1的中间区域相互作用，包括富含甘氨酸-赖氨酸的区域，并且在体内与YY1和BAP1形成三元配合物是必不可少的。BAP1以酶活性依赖的方式激活转录，并调节参与许多细胞过程的多种基因的表达。我们进一步发现，BAP1和HCF-1被YY1募集到cox7c基因的启动子上，cox7c基因编码一种线粒体蛋白，在这里用作BAP1激活基因表达的模型。我们的发现(i)建立了BAP1与调节细胞生长和增殖的基因转录控制之间的直接联系，（ii）揭示了涉及泛素信号传导的转录调节新机制。
The candidate tumor suppressor BAP1 is a deubiquitinating enzyme (DUB) involved in the regulation of cell proliferation, although the molecular mechanisms governing its function remain poorly defined. BAP1 was recently shown to interact with and deubiquitinate the transcriptional regulator host cell factor 1 (HCF-1). Here we show that BAP1 assembles multiprotein complexes containing numerous transcription factors and cofactors, including HCF-1 and the transcription factor Yin Yang 1 (YY1). Through its coiled-coil motif, BAP1 directly interacts with the zinc fingers of YY1. Moreover, HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. BAP1 activates transcription in an enzymatic-activity-dependent manner and regulates the expression of a variety of genes involved in numerous cellular processes. We further show that BAP1 and HCF-1 are recruited by YY1 to the promoter of the cox7c gene, which encodes a mitochondrial protein used here as a model of BAP1-activated gene expression. Our findings (i) establish a direct link between BAP1 and the transcriptional control of genes regulating cell growth and proliferation and (ii) shed light on a novel mechanism of transcription regulation involving ubiquitin signaling.