Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBV in vitro and in vivo.
Interferon-stimulated gene of 20 kDa protein (ISG20) degrades RNA of hepatitis B virus to impede the replication of HBV in vitro and in vivo.
复制标题
DOI：
10.18632/oncotarget.11907
复制
发表时间：
2016-10-18
期刊：
影响因子：
--
通讯作者：
Seya T
中科院分区：
文献类型：
--
作者：
Leong CR;Funami K;Oshiumi H;Mengao D;Takaki H;Matsumoto M;Aly HH;Watashi K;Chayama K;Seya T
B型肝炎病毒（HBV）几乎不诱导宿主干扰素（IFN）刺激基因（ISG），这允许HBV在永生化小鼠肝细胞中有效复制，就像人肝细胞一样。在此我们发现，转染Isg 20质粒可以显著抑制HBV感染肝细胞中的HBV复制，而与IRF 3或IFN启动子的激活无关。因此，转染Isg 20可有效根除感染肝细胞中的HBV。HBV基因组或HBV pgRNA的ε-茎（活性pgRNA部分）的转染未能在肝细胞中诱导Isg 20，而对照polyI：C（病毒dsRNA类似物模拟物）激活MAVS途径，导致I型IFN产生，然后通过IFN-α/β受体（IFNAR）产生ISGsg 20。结论：IFN-α诱导了肝细胞Isg 20的表达，并部分抑制了HBV的复制。印迹法追踪HBV RNA、DNA和蛋白质结果表明，ISG 20表达降低了HBV转染细胞中HBV RNA和复制DNA的含量，从而降低了HBs抗原的产生和病毒滴度。ISG 20的核酸外切酶结构域主要参与HBV-RNA的降解。在体内流体动力学注射中，ISG 20对于抑制HBV复制而不降解肝脏中的宿主RNA至关重要。总之，ISG 20作为一种先天性抗HBV效应子，选择性降解HBV RNA并阻断感染性HBV颗粒的复制。ISG 20可能是IFN治疗中改善慢性HBV感染的关键效应子。
Hepatitis B virus (HBV) barely induces host interferon (IFN)-stimulated genes (ISGs), which allows efficient HBV replication in the immortalized mouse hepatocytes as per human hepatocytes. Here we found that transfection of Isg20 plasmid robustly inhibits the HBV replication in HBV-infected hepatocytes irrespective of IRF3 or IFN promoter activation. Transfection of Isg20 is thus effective to eradicate HBV in the infected hepatocytes. Transfection of HBV genome or ε-stem of HBV pgRNA (active pgRNA moiety) failed to induce Isg20 in the hepatocytes, while control polyI:C (a viral dsRNA analogue mimic) activated MAVS pathway leading to production of type I IFN and then ISGsg20 via the IFN-α/β receptor (IFNAR). Consistently, addition of IFN-α induced Isg20 and partially suppressed HBV replication in hepatocytes. Chasing HBV RNA, DNA and proteins by blotting indicated that ISG20 expression decreased HBV RNA and replicative DNA in HBV-transfected cells, which resulted in low HBs antigen production and virus titer. The exonuclease domains of ISG20 mainly participated in HBV-RNA decay. In vivo hydrodynamic injection, ISG20 was crucial for suppressing HBV replication without degrading host RNA in the liver. Taken together, ISG20 acts as an innate anti-HBV effector that selectively degrades HBV RNA and blocks replication of infectious HBV particles. ISG20 would be a critical effector for ameliorating chronic HBV infection in the IFN therapy.