Balasubramanian Anuradha, Ganju Ramesh K, Groopman Jerome E
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
J Infect Dis. 2006 Sep 1;194(5):670-81. doi: 10.1086/505708. Epub 2006 Jul 18.
Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have progressive liver disease that frequently leads to cirrhosis and death. We previously showed that hepatocytes exposed to HCV and HIV envelope proteins undergo apoptosis via an innocent-bystander mechanism as a result of the cell surface binding of these proteins, independent of direct viral infection. Here, we have defined the mechanism of this hepatocytic apoptosis. We observed enhanced signal transducer and activator of transcription factor 1 (STAT1) activation and phosphorylation after costimulation with HCV-E2 and HIV-gp120. Moreover, inhibitor studies indicated that Lyn kinase, p38 mitogen-activated protein kinase, and protein kinase C delta might be involved in STAT1 phosphorylation. To elucidate the downstream STAT1-mediated signaling, we overexpressed wild-type STAT1 alpha and the C-terminal domain-deleted mutant STAT1 beta . STAT1 alpha overexpression increased cell apoptosis and Fas ligand expression, compared with STAT1 beta overexpression. STAT1 alpha also enhanced the release of cytochrome c from the mitochondria and caspase-3 activity. These studies indicate that the HCV/HIV envelope proteins cooperatively induce hepatocytic apoptosis by activating a novel downstream STAT1 signaling pathway.
丙型肝炎病毒（HCV）和人类免疫缺陷病毒（HIV）合并感染的患者会出现进行性肝病，常导致肝硬化和死亡。我们之前表明，暴露于HCV和HIV包膜蛋白的肝细胞会由于这些蛋白在细胞表面的结合而通过旁观者机制发生凋亡，这与直接病毒感染无关。在此，我们确定了这种肝细胞凋亡的机制。我们观察到，在用HCV-E2和HIV-gp120共刺激后，信号转导和转录激活因子1（STAT1）的激活和磷酸化增强。此外，抑制剂研究表明，Lyn激酶、p38丝裂原活化蛋白激酶和蛋白激酶Cδ可能参与了STAT1的磷酸化。为了阐明下游STAT1介导的信号传导，我们过表达了野生型STAT1α和C末端结构域缺失的突变体STAT1β。与STAT1β过表达相比，STAT1α过表达增加了细胞凋亡和Fas配体表达。STAT1α还增强了细胞色素c从线粒体的释放和caspase-3活性。这些研究表明，HCV/HIV包膜蛋白通过激活一条新发现的下游STAT1信号通路协同诱导肝细胞凋亡。
