Liang Guoxin, Liu Guangyan, Kitamura Kouichi, Wang Zhe, Chowdhury Sajeda, Monjurul Ahasan Md, Wakae Kousho, Koura Miki, Shimadu Miyuki, Kinoshita Kazuo, Muramatsu Masamichi
Department of Molecular Genetics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Department of Microbiology and Immunology, Columbia University, New York, New York, United States of America.
Department of Molecular Genetics, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
PLoS Pathog. 2015 Apr 2;11(4):e1004780. doi: 10.1371/journal.ppat.1004780. eCollection 2015 Apr.
Transforming growth factor (TGF)-β inhibits hepatitis B virus (HBV) replication although the intracellular effectors involved are not determined. Here, we report that reduction of HBV transcripts by TGF-β is dependent on AID expression, which significantly decreases both HBV transcripts and viral DNA, resulting in inhibition of viral replication. Immunoprecipitation reveals that AID physically associates with viral P protein that binds to specific virus RNA sequence called epsilon. AID also binds to an RNA degradation complex (RNA exosome proteins), indicating that AID, RNA exosome, and P protein form an RNP complex. Suppression of HBV transcripts by TGF-β was abrogated by depletion of either AID or RNA exosome components, suggesting that AID and the RNA exosome involve in TGF-β mediated suppression of HBV RNA. Moreover, AID-mediated HBV reduction does not occur when P protein is disrupted or when viral transcription is inhibited. These results suggest that induced expression of AID by TGF-β causes recruitment of the RNA exosome to viral RNP complex and the RNA exosome degrades HBV RNA in a transcription-coupled manner.
转化生长因子（TGF）-β可抑制乙型肝炎病毒（HBV）复制，尽管其中涉及的细胞内效应因子尚未明确。在此，我们报告TGF-β介导的HBV转录本减少依赖于AID的表达，AID可显著降低HBV转录本和病毒DNA水平，进而抑制病毒复制。免疫沉淀显示，AID与病毒P蛋白存在物理结合，P蛋白可与一种名为ε的特定病毒RNA序列结合。AID还与一种RNA降解复合物（RNA外切体蛋白）结合，这表明AID、RNA外切体和P蛋白形成了一种核糖核蛋白复合物（RNP复合物）。通过敲除AID或RNA外切体组分可消除TGF-β对HBV转录本的抑制作用，这表明AID和RNA外切体参与了TGF-β介导的HBV RNA抑制过程。此外，当P蛋白被破坏或病毒转录受到抑制时，AID介导的HBV减少作用不会发生。这些结果表明，TGF-β诱导的AID表达会促使RNA外切体募集至病毒RNP复合物，且RNA外切体以转录偶联的方式降解HBV RNA。
