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Effects of HOIL-1 ubiquitin ligase complex on the physiological function of hepatitis B virus X protein

HOIL-1泛素连接酶复合物对乙型肝炎病毒X蛋白生理功能的影响

基本信息

批准号：
15590279
负责人：
TOKUNAGA Fuminori
金额：
$ 2.43万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590279/
关键词：
ubiquitin hepatitis B virus NF-κB transactivation henatocarcinoma

项目摘要

In the course of studies on iron-dependent degradation of iron regulatory protein 2 (IRP2), we identified a RING-type ubiquitin ligase, HOIL-1, that specifically ubiquitinates heme-oxidized IRP2. HOIL-1 had also been characterized as a hepatitis B virus X protein (HBx)-associating protein, although its function was unrevealed. We showed that HOIL-1 associates with HBx through its ubiquitin-like domain, resulting in the partial suppression of transactivation activity. Recently, we further found that HOIL-1 forms a high molecular mass complex with another uncharacterized RING-type containing protein. To investigate the role of HOIL-1 ligase complex on the pathogenesis of hepatitis B virus, we analyzed the effect of HOIL-1 complex on the transactivation activity of HBx. In HepG2 cells, co-expression of HOIL-1 complex with HBx caused to drastic increase (>10-fold) in 6x NF-κB-luciferase (Luc) reporter activity, although Rous sarcoma virus (RSV)-Luc activity was unaffected, suggesting that HBx specifically activates NF-κB pathway through the association with HOIL-1 complex. HOIL-1 complex lacking ubiquitin ligase activity had little effect on the NF-κB-Luc activity of HBx. These results suggested that HBx associates with the HOIL-1 ubiquitin ligase complex and that induces an aberrant activation of NF-κB pathway through ubiquitination activity. The mechanism might play an important role on the hepatocarcinogenesis by hepatitis B virus.

在研究铁调节蛋白2（IRP 2）的铁依赖性降解过程中，我们鉴定了一种RING型泛素连接酶HOIL-1，它特异性地泛素化血红素氧化的IRP 2。HOIL-1也被鉴定为B病毒X蛋白（HBx）相关蛋白，尽管其功能尚未被揭示。我们发现HOIL-1通过其泛素样结构域与HBx结合，导致反式激活活性的部分抑制。最近，我们进一步发现HOIL-1与另一种未知的RING型蛋白形成高分子量复合物。为探讨HOIL-1连接酶复合物在B型肝炎病毒发病机制中的作用，我们分析了HOIL-1复合物对HBx反式激活活性的影响。在HepG 2细胞中，HOIL-1复合物与HBx的共表达导致6x NF-κ B-荧光素酶（Luc）报告基因活性急剧增加（>10倍），尽管劳斯肉瘤病毒（RSV）-Luc活性不受影响，表明HBx通过与HOIL-1复合物的结合特异性激活NF-κB途径。缺乏泛素连接酶活性的HOIL-1复合物对HBx的NF-κB-Luc活性影响不大。这些结果表明，HBx与HOIL-1泛素连接酶复合物结合，并通过泛素化活性诱导NF-κB通路的异常激活。该机制可能在B型肝炎病毒致肝癌过程中起重要作用。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of endoplasmic reticulum-associated degradation of a protein S mutant identified in a family of quantitative protein S deficiency.

在定量蛋白 S 缺陷家族中鉴定的蛋白 S 突变体的内质网相关降解的表征。

DOI：
发表时间：
2005
期刊：
Thromb.Res. (in press)
影响因子：
0
作者：
Hitomi HAYABUCHI;Manami HISANO;Yasuko MATSUNAGA;Yasumi Kimura;Ohnaka Keizo;Tsuda Hiroko
通讯作者：
Tsuda Hiroko

Yamanaka, K. et al.: "Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2"Nature Cell Biology. 5・(4). 336-340 (2003)

Yamanaka，K.等：“识别氧化IRP2的泛素蛋白连接酶”Nature Cell Biology 5·(4)336-340(2003)。