College of Life Sciences, Modern Virology Center, Wuhan University, Wuhan 430072, China.
Cell Mol Immunol. 2010 Sep;7(5):341-8. doi: 10.1038/cmi.2010.36. Epub 2010 Aug 16.
Viral RNAs produced during viral infection are recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). A central adapter protein downstream of RIG-I and MDA5 is the mitochondrial membrane protein virus-induced signaling adaptor (VISA), which mediates the induction of type I interferons (IFNs) through the activation of transcription factors such as nuclear factor-kappaB (NF-kappaB) and IFN-regulatory factor-3 (IRF3). Here we found that hepatitis B virus (HBV)-encoded X protein (HBx) acts as an inhibitor of virus-triggered IRF3 activation and IFN-beta induction. Reporter and plaque assays indicate that HBx inhibits signaling by components upstream but not downstream of VISA. Immunoprecipitation experiments indicate that HBx interacts with VISA and disrupts the association of VISA with its upstream and downstream components. These findings suggest that HBx acts as a suppressor of virus-triggered induction of type I IFNs, which explains the observation that HBV causes transient and chronic infection in hepatocytes but fails to activate the pattern recognition receptor-mediated IFN induction pathways.
病毒感染期间产生的病毒 RNA 被细胞质 RNA 解旋酶视黄酸诱导基因-I（RIG-I）和黑色素瘤分化相关基因 5（MDA5）识别。RIG-I 和 MDA5 下游的一个中央衔接蛋白是线粒体膜蛋白病毒诱导信号衔接蛋白（VISA），它通过激活转录因子（如核因子-κB（NF-κB）和干扰素调节因子-3（IRF3））来介导 I 型干扰素（IFNs）的诱导。在这里，我们发现乙型肝炎病毒（HBV）编码的 X 蛋白（HBx）作为病毒触发的 IRF3 激活和 IFN-β诱导的抑制剂。报告基因和蚀斑测定表明，HBx 抑制 VISA 上游而不是下游成分的信号转导。免疫沉淀实验表明，HBx 与 VISA 相互作用并破坏 VISA 与其上下游成分的结合。这些发现表明 HBx 作为 I 型 IFNs 病毒触发诱导的抑制剂发挥作用，这解释了 HBV 导致肝细胞中短暂和慢性感染但未能激活模式识别受体介导的 IFN 诱导途径的观察结果。
