Modulation of retinoid signaling by a cytoplasmic viral protein via sequestration of Sp110b, a potent transcriptional corepressor of retinoic acid receptor, from the nucleus
Modulation of retinoid signaling by a cytoplasmic viral protein via sequestration of Sp110b, a potent transcriptional corepressor of retinoic acid receptor, from the nucleus
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DOI：
10.1128/mcb.23.21.7498-7509.2003
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发表时间：
2003-11-01
影响因子：
5.3
通讯作者：
Shimotohno, K
中科院分区：
文献类型：
--
作者：
Watashi, K;Hijikata, M;Shimotohno, K
丙型肝炎病毒（HCV）核心蛋白（core）在HCV感染引起的慢性肝病的发展中起着重要作用。我们已经发现，核心敏化全反式维甲酸（ATRA）诱导的MCF-7细胞的细胞死亡。视黄酸受体α（RAR α）介导的核心转录的激活也见于所有测试的细胞系。通过使用酵母双杂交系统，我们确定Sp110 b作为核心相互作用的细胞因子的候选者。虽然Sp110 b的功能仍然未知，但我们观察到Sp110 b与RAR α相互作用并抑制RAR α介导的转录。这些数据表明，Sp110 b是一个转录辅因子负调控RAR α介导的转录。RNA干扰介导的内源性Sp110 b水平的降低抑制了核心激活RAR α介导的转录的能力，这表明Sp110 b在该途径中起着重要作用。Sp110 b的正常核亚细胞定位被改变的分子相互作用与核心的内质网的细胞质表面。这一证据提示了一种模型，在该模型中，核心将Sp110 b与细胞核隔离，并使其辅阻遏物功能失活，从而激活RAR α介导的转录。这些发现可能描述了一种新的系统，其中细胞质病毒蛋白调节宿主细胞转录。
Hepatitis C virus (HCV) core protein (core) plays a significant role in the development of chronic liver diseases caused by HCV infection. We have discovered that the core sensitized all-trans-retinoic acid (ATRA)-induced cell death in MCF-7 cells. Activation of retinoic acid receptor alpha (RARalpha)-mediated transcription by the core was also seen in all the cell lines tested. By use of a yeast two-hybrid system, we identified Sp110b as a candidate for a core-interacting cellular factor. Although the function of Sp110b has remained unknown, we observed that Sp110b interacts with RARalpha and suppresses RARalpha-mediated transcription. These data suggest that Sp110b is a transcriptional cofactor negatively regulating RARalpha-mediated transcription. RNA interference-mediated reduction of endogenous Sp110b levels depressed the ability of the core to activate RARalpha-mediated transcription, suggesting an essential role for Sp110b in this pathway. The normal nuclear subcellular localization of Sp110b was altered by molecular interaction with the core to the cytoplasmic surface of the endoplasmic reticulum. This evidence suggests a model in which the core sequesters Sp110b from the nucleus and inactivates its corepressor function to activate RARalpha-mediated transcription. These findings likely describe a novel system in which a cytoplasmic viral protein regulates host cell transcription.