Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression
Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression
复制标题
乙型肝炎病毒核心蛋白通过阻断DR5表达抑制TRAIL诱导的肝细胞凋亡
DOI：
10.1038/cdd.2008.144
复制
发表时间：
2009-02-01
影响因子：
12.4
通讯作者：
Sun, W.
中科院分区：
文献类型：
--
作者：
Du, J.;Liang, X.;Sun, W.
B型肝炎病毒（HBV）导致全世界数亿人慢性肝炎，其最终可导致肝细胞癌（HCC）。HBV持续存在的分子机制还不清楚。肿瘤坏死因子相关凋亡诱导配体TRAIL最近被认为与HBV感染时肝细胞死亡有关。我们在这里报告说，HBV核心蛋白（HBc）是一个有效的抑制TRAIL诱导的细胞凋亡。过表达HBc可显著降低TRAIL诱导的人肝癌细胞凋亡，而在转染HBV基因组的肝癌细胞中敲低HBc表达可增强TRAIL诱导的人肝癌细胞凋亡，当HBc存在于同一细胞中时，HBc可阻断HBV X蛋白（HBx）的促凋亡作用。HBc表达细胞对TRAIL诱导的细胞凋亡的抗性与死亡受体5（DR 5）表达的显著降低相关。转染后，HBc显着抑制人DR 5基因的启动子活性。重要的是，HBc基因转移抑制了HBV诱导的肝炎小鼠模型中的肝细胞死亡;在慢性肝炎患者中，肝脏中的DR 5表达显著降低。这些结果表明，HBc可能通过阻断DR 5的表达来阻止肝细胞凋亡，这反过来又有助于慢性肝炎和HCC的发展。他们还质疑HBc疫苗的潜在副作用。
Hepatitis B virus (HBV) causes chronic hepatitis in hundreds of millions of people worldwide, which can eventually lead to hepatocellular carcinoma (HCC). The molecular mechanisms underlying HBV persistence are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in hepatocyte death during HBV infection. We report here that the HBV core protein (HBc) is a potent inhibitor of TRAIL-induced apoptosis. Overexpressing HBc significantly decreased TRAIL-induced apoptosis of human hepatoma cells, whereas knocking-down HBc expression in hepatoma cells transfected with HBV genome enhanced it. When present in the same cell, HBc blocked the pro-apoptotic effect of the HBV X protein (HBx). The resistance of HBc-expressing cells to TRAIL-induced apoptosis was associated with a significant reduction in death receptor 5 (DR5) expression. Upon transfection, HBc significantly repressed the promoter activity of the human DR5 gene. Importantly, HBc gene transfer inhibited hepatocyte death in a mouse model of HBV-induced hepatitis; and in patients with chronic hepatitis, DR5 expression in the liver was significantly reduced. These results indicate that HBc may prevent hepatocytes from TRAIL-induced apoptosis by blocking DR5 expression, which in turn contributes to the development of chronic hepatitis and HCC. They also call into question the potential side effects of HBc-based vaccines.