Du J, Liang X, Liu Y, Qu Z, Gao L, Han L, Liu S, Cui M, Shi Y, Zhang Z, Yu L, Cao L, Ma C, Zhang L, Chen Y, Sun W
Department of Immunology, School of Medicine, Shandong University, Jinan, China.
Cell Death Differ. 2009 Feb;16(2):219-29. doi: 10.1038/cdd.2008.144. Epub 2008 Oct 17.
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.
乙肝病毒（HBV）在全球数亿人中引发慢性肝炎，最终可能导致肝细胞癌（HCC）。HBV持续存在的分子机制尚未完全明确。肿瘤坏死因子相关凋亡诱导配体（TRAIL）最近被认为与HBV感染期间的肝细胞死亡有关。我们在此报告，HBV核心蛋白（HBc）是TRAIL诱导凋亡的有效抑制剂。过表达HBc可显著降低TRAIL诱导的人肝癌细胞凋亡，而在转染了HBV基因组的肝癌细胞中敲低HBc表达则会增强凋亡。当存在于同一细胞中时，HBc会阻断HBV X蛋白（HBx）的促凋亡作用。表达HBc的细胞对TRAIL诱导凋亡的抗性与死亡受体5（DR5）表达的显著降低有关。转染后，HBc显著抑制人DR5基因的启动子活性。重要的是，HBc基因转移可抑制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DR5表达也显著降低。这些结果表明，HBc可能通过阻断DR5表达来防止肝细胞发生TRAIL诱导的凋亡，这反过来又促进了慢性肝炎和HCC的发展。它们还对基于HBc的疫苗的潜在副作用提出了质疑。
