Inhibition of hepatitis B virus replication by the host zinc finger antiviral protein.
Inhibition of hepatitis B virus replication by the host zinc finger antiviral protein.
复制标题
宿主锌指抗病毒蛋白抑制乙型肝炎病毒复制
DOI：
10.1371/journal.ppat.1003494
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Mao R;Nie H;Cai D;Zhang J;Liu H;Yan R;Cuconati A;Block TM;Guo JT;Guo H
锌指抗病毒蛋白（ZAP）是一种哺乳动物宿主限制因子，通过与病毒RNA中的ZAP反应元件（ZRE）相互作用并募集外泌体降解RNA底物来抑制多种RNA病毒（包括逆转录病毒、甲病毒和丝状病毒）的复制。B型肝炎病毒（HBV）是一种副逆转录病毒，通过逆转录病毒前基因组（pg）RNA前体来复制其基因组DNA。在这里，我们证明了人类ZAP的两种亚型（hZAP-L和-S）通过下调病毒pgRNA的转录后水平来抑制HBV在人肝细胞衍生细胞中的复制。从机制上讲，hZAP的N端锌指基序负责HBV RNA的还原，四个锌指基序的完整性是ZAP与HBV RNA结合并实现其抗病毒功能所必需的。将赋予病毒RNA对ZAP介导的RNA降解的易感性的ZRE序列定位于HBV pgRNA的末端冗余区（nt 1820-1918）。与其作为宿主限制因子和HBV感染的先天免疫介质的作用一致，ZAP在培养的原代人肝细胞和肝细胞衍生的细胞中在IFN-α处理或IPS-1活化后上调，并且在免疫活跃期的B肝炎患者的肝脏中上调。ZAP表达的敲低增加了HBV RNA的水平，并部分减弱了IPS-1在细胞培养中引起的抗病毒作用。总之，我们证明了ZAP是一种内在的宿主抗病毒因子，通过下调病毒RNA具有抗HBV活性，并且ZAP在HBV复制的先天控制中起作用。因此，我们的研究结果揭示了病毒-宿主相互作用，病毒的发病机制和抗病毒的方法。
The zinc finger antiviral protein (ZAP) is a mammalian host restriction factor that inhibits the replication of a variety of RNA viruses, including retroviruses, alphaviruses and filoviruses, through interaction with the ZAP-responsive elements (ZRE) in viral RNA, and recruiting the exosome to degrade RNA substrate. Hepatitis B virus (HBV) is a pararetrovirus that replicates its genomic DNA via reverse transcription of a viral pregenomic (pg) RNA precursor. Here, we demonstrate that the two isoforms of human ZAP (hZAP-L and -S) inhibit HBV replication in human hepatocyte-derived cells through posttranscriptional down-regulation of viral pgRNA. Mechanistically, the zinc finger motif-containing N-terminus of hZAP is responsible for the reduction of HBV RNA, and the integrity of the four zinc finger motifs is essential for ZAP to bind to HBV RNA and fulfill its antiviral function. The ZRE sequences conferring the susceptibility of viral RNA to ZAP-mediated RNA decay were mapped to the terminal redundant region (nt 1820–1918) of HBV pgRNA. In agreement with its role as a host restriction factor and as an innate immune mediator for HBV infection, ZAP was upregulated in cultured primary human hepatocytes and hepatocyte-derived cells upon IFN-α treatment or IPS-1 activation, and in the livers of hepatitis B patients during immune active phase. Knock down of ZAP expression increased the level of HBV RNA and partially attenuated the antiviral effect elicited by IPS-1 in cell cultures. In summary, we demonstrated that ZAP is an intrinsic host antiviral factor with activity against HBV through down-regulation of viral RNA, and that ZAP plays a role in the innate control of HBV replication. Our findings thus shed light on virus-host interaction, viral pathogenesis, and antiviral approaches.
登录
查看更多内容
ZAP N 端结构域的结构表明锌指蛋白如何识别复杂的 RNA
影响因子：
16.8
作者：
Chen, Shoudeng;Xu, Yihui;Liu, Yingfang
通讯作者：
Liu, Yingfang
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S
影响因子：
--
作者：
Chisari, F. V.;Isogawa, M.;Wieland, S. F.
通讯作者：
Wieland, S. F.
影响因子：
5.4
作者：
Guo, Haitao;Zhou, Tianlun;Guo, Ju-Tao
通讯作者：
Guo, Ju-Tao
影响因子：
13.5
作者：
Hoesel, Marianna;Quasdorff, Maria;Protzer, Ulrike
通讯作者：
Protzer, Ulrike