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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca~(2+) increase and cell death in Caenorhabditis elegans
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Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca~(2+) increase and cell death in Caenorhabditis elegans

机译：乙型肝炎病毒X蛋白靶向Bcl-2蛋白CED-9，诱导秀丽隐杆线虫细胞内Ca〜（2+）增加和细胞死亡

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摘要

HBx is a multifunctional hepatitis B virus (HBV) protein that is crucial for HBV infection and pathogenesis and a contributing cause of hepatocyte carcinogenesis. However, the host targets and mechanisms of action of HBx are poorly characterized. We show here that expression'of HBx in Caenorhabditis elegans induces both necrotic and apoptotic cell death, mimicking an early event of liver infection by HBV. Genetic and biochemical analyses indicate that HBx interacts directly with the B-cell lymphoma 2 (Bcl-2) ho-molog CED-9 (cell death abnormal) through a Bcl-2 homology 3 (BH3)-like motif to trigger both cytosolic Ca~(2+) increase and cell death. Importantly, Bcl-2 can substitute for CED-9 in mediating HBx-induced cell killing in C. elegans, suggesting that CED-9 and Bcl-2 are conserved cellular targets of HBx. A genetic suppressor screen of HBx-induced cell death has produced many mutations, including mutations in key regulators from both apoptosis and necrosis pathways, indicating that this screen can identify new apoptosis and necrosis genes. Our results suggest that C. elegans could serve as an animal model for identifying crucial host factors and signaling pathways of HBx and aid in development of strategies to treat HBV-induced liver disorders.
机译：HBx是一种多功能的乙型肝炎病毒（HBV）蛋白，对HBV感染和发病机制至关重要，也是肝细胞癌变的重要原因。但是，HBx的宿主目标和作用机制的特征较差。我们在这里显示，秀丽隐杆线虫中HBx的表达诱导坏死性和凋亡性细胞死亡，模仿了HBV引起的肝感染的早期事件。遗传和生化分析表明，HBx通过Bcl-2同源3（BH3）样基序直接与B细胞淋巴瘤2（Bcl-2）同源CED-9（细胞死亡异常）相互作用，从而触发两个胞质Ca 〜（2+）增加和细胞死亡。重要的是，Bcl-2可以替代CED-9介导秀丽隐杆线虫中HBx诱导的细胞杀伤，表明CED-9和Bcl-2是HBx的保守细胞靶标。 HBx诱导的细胞死亡的遗传抑制物筛选产生了许多突变，包括来自凋亡和坏死途径的关键调控因子的突变，表明该筛选可以识别新的凋亡和坏死基因。我们的研究结果表明，秀丽隐杆线虫可以作为动物模型，用于鉴定关键的宿主因子和HBx信号通路，并有助于制定治疗HBV引起的肝病的策略。

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    Xin Geng; Brian L Harry; Qinghua Zhou; Riley Robert Skeen-Gaar; Xiao Ge; Eui Seung Lee; Shohei Mitani; Ding Xue;

  • 作者单位

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309;

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309;

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309;

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309;

    School of Life Sciences, Tsinghua University, Beijing 100084, China;

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309;

    Department of Physiology, Tokyo Women's Medical University, School of Medicine, Tokyo, 162-8666, Japan;

    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309,School of Life Sciences, Tsinghua University, Beijing 100084, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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