Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation.
Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation.
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乙型肝炎病毒通过 HBx 介导的 Nrf2 激活刺激 G6PD 表达
DOI：
10.1038/cddis.2015.322
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发表时间：
2015-11-19
影响因子：
9
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Liu B;Fang M;He Z;Cui D;Jia S;Lin X;Xu X;Zhou T;Liu W
代谢重编程是癌症生理变化的标志。癌细胞主要利用糖酵解进行细胞代谢，使细胞利用糖酵解中间产物进行大分子生物合成，以满足细胞增殖的需要。在这里，我们表明，葡萄糖-6-磷酸脱氢酶（G6 PD），第一和戊糖磷酸途径的限速酶，是高度表达在慢性B肝炎病毒（HBV）感染的人肝和HBV相关的肝癌，连同转录因子Nrf 2的活性升高。在肝细胞中，HBV通过其X蛋白（HBx）以Nrf 2激活依赖性途径刺激G6 PD的表达。HBx与衔接蛋白p62的乌巴和PB 1结构域结合，并增强p62与Nrf 2阻遏物Keap 1之间的相互作用，从而在细胞质中形成HBx-p62-Keap 1复合物。HBx-p62-Keap 1复合物的聚集从Nrf 2劫持Keap 1，导致Nrf 2的激活，从而导致G6 PD转录。我们的数据表明，HBV通过HBx介导的Nrf 2激活上调G6 PD表达。这意味着HBV对肝细胞葡萄糖代谢重编程的潜在影响，这可能在HBV相关肝癌的发展中具有重要意义。
Metabolic reprogramming is a hallmark of physiological changes in cancer. Cancer cells primarily apply glycolysis for cell metabolism, which enables the cells to use glycolytic intermediates for macromolecular biosynthesis in order to meet the needs of cell proliferation. Here, we show that glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is highly expressed in chronic hepatitis B virus (HBV)-infected human liver and HBV-associated liver cancer, together with an elevated activity of the transcription factor Nrf2. In hepatocytes, HBV stimulates by its X protein (HBx) the expression of G6PD in an Nrf2 activation-dependent pathway. HBx associates with the UBA and PB1 domains of the adaptor protein p62 and augments the interaction between p62 and the Nrf2 repressor Keap1 to form HBx–p62–Keap1 complex in the cytoplasm. The aggregation of HBx–p62–Keap1 complexes hijacks Keap1 from Nrf2 leading to the activation of Nrf2 and consequently G6PD transcription. Our data suggest that HBV upregulates G6PD expression by HBx-mediated activation of Nrf2. This implies a potential effect of HBV on the reprogramming of the glucose metabolism in hepatocytes, which may be of importance in the development of HBV-associated hepatocarcinoma.