TGF-β suppression of HBV RNA through AID-dependent recruitment of an RNA exosome complex.
TGF-β suppression of HBV RNA through AID-dependent recruitment of an RNA exosome complex.
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DOI：
10.1371/journal.ppat.1004780
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发表时间：
2015-04
期刊：
影响因子：
6.7
通讯作者：
Muramatsu M
中科院分区：
文献类型：
--
作者：
Liang G;Liu G;Kitamura K;Wang Z;Chowdhury S;Monjurul AM;Wakae K;Koura M;Shimadu M;Kinoshita K;Muramatsu M
转化生长因子(TGF)-β抑制乙型肝炎病毒（HBV）的复制，尽管细胞内效应尚未确定。在这里，我们报道了TGF-β对HBV转录物的减少依赖于AID的表达，而AID的表达会显著降低HBV转录物和病毒DNA，从而抑制病毒复制。免疫沉淀显示AID与病毒P蛋白物理结合，该蛋白结合到称为epsilon的特定病毒RNA序列。AID还与RNA降解复合物（RNA外泌体蛋白）结合，表明AID、RNA外泌体和P蛋白形成RNP复合物。通过去除AID或RNA外泌体成分，TGF-β对HBV转录物的抑制作用被消除，这表明AID和RNA外泌体参与了TGF-β介导的HBV RNA抑制。此外，当P蛋白被破坏或病毒转录被抑制时，艾滋病介导的HBV减少不会发生。这些结果表明，TGF-β诱导AID的表达导致RNA外泌体向病毒RNP复合体募集，RNA外泌体以转录偶联的方式降解HBV RNA。HBV是肝细胞癌的病因之一。最近的研究表明，APOBEC脱氨酶家族的成员是抑制病毒复制的抗病毒因子，如HIV-1和HBV。APOBEC3G通过新生DNA的超突变或抑制逆转录来抑制病毒复制。最近的研究表明，APOBEC家族的另一成员AID可以限制利用逆转录进行复制的病毒和逆转录转座子。然而，人们对艾滋病的抗病毒机制知之甚少。TGF-β是一种参与抑制HBV复制的多效细胞因子，但其抗HBV活性的机制尚不清楚。在本研究中，我们发现AID对TGF-β的抗hbv活性有影响。进一步的研究表明，AID与含有逆转录酶的病毒RNP复合物物理结合，并将RNA降解体（RNA外泌体）招募到RNP复合物中以降解病毒RNA。据我们所知，这项研究首次揭示了一种新的抗病毒途径，其中AID通过将RNA外泌体拴在病毒逆转录酶/RNA复合物上来触发病毒RNA降解。病毒RNA可能是APOBEC抗病毒活性的另一个靶点。
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. HBV is one of the causative factors of hepatocellular carcinoma. Recent studies have shown that the members of the APOBEC deaminase family are antiviral factors that suppress the replication of viruses, such as HIV-1 and HBV. APOBEC3G suppresses viral replication by either hypermutation of nascent DNA or inhibition of reverse transcription. Recent studies have been suggested that AID, another APOBEC family member, restricts viruses and retrotransposons that use reverse transcription for their replication. However, little is known about the antiviral mechanisms of AID. TGF-β is a pleiotropic cytokine involved in the suppression of HBV replication, but the mechanism underlying its anti-HBV activity is unclear. In this study, we found that AID plays a role in the anti-HBV activity of TGF-β. Further study revealed that AID physically associates with a viral RNP complex containing reverse transcriptase and recruits the RNA degradosome (RNA exosome) to the RNP complex to degrade the viral RNA. To the best of our knowledge, this study is the first to reveal a novel antiviral pathway in which AID triggers viral RNA degradation by tethering the RNA exosome to the viral reverse transcriptase/RNA complex. Viral RNA may be another target for APOBEC antiviral activity.
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影响因子：
8
作者：
Endo, Y.;Marusawa, H.;Chiba, T.
通讯作者：
Chiba, T.
影响因子：
13.5
作者：
Chou, Yu-Chi;Chen, Mong-Liang;Chang, Chungming
通讯作者：
Chang, Chungming
影响因子：
6.7
作者：
Kitamura K;Wang Z;Chowdhury S;Simadu M;Koura M;Muramatsu M
通讯作者：
Muramatsu M
宿主锌指抗病毒蛋白抑制乙型肝炎病毒复制
影响因子：
6.7
作者：
Mao R;Nie H;Cai D;Zhang J;Liu H;Yan R;Cuconati A;Block TM;Guo JT;Guo H
通讯作者：
Guo H
影响因子：
14.9
作者：
MacDuff DA;Demorest ZL;Harris RS
通讯作者：
Harris RS