Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein.
Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein.
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DOI：
10.1371/journal.ppat.1007166
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发表时间：
2018-07
期刊：
影响因子：
6.7
通讯作者：
Lin YL
中科院分区：
文献类型：
--
作者：
Chiu HP;Chiu H;Yang CF;Lee YL;Chiu FL;Kuo HC;Lin RJ;Lin YL
CCCH型锌指抗病毒蛋白(ZAP)是一种宿主因子，主要通过RNA降解、翻译抑制和先天免疫反应来抑制多种病毒的感染。到目前为止，据报道只有一种黄病毒--黄热病病毒对ZAP具有抗药性。在这里，我们研究了人ZAP(ZAP-L和ZAP-S)对三种黄病毒，日本脑炎病毒，登革病毒和寨卡病毒的抗病毒作用。ZAP过表达可阻断JEV的感染，但不能阻断DENV或ZIKV的感染，内源性ZAP的缺失可促进JEV的复制。ZAP阻碍了JEV的翻译，并靶向病毒RNA进行3‘-5’RNA外切体介导的降解。ZAP的锌指基序是RNA靶向和抗JEV活性所必需的。JEV3‘-非编码区，特别是在哑铃状结构和CG二核苷酸含量较高的区域，被定位为结合ZAP并增加对ZAP的敏感性。综上所述，我们确定乙脑病毒是第一种对ZAP敏感的黄病毒。ZAP可能作为一种内在的抗病毒因子，通过与特异的RNA结合来对抗JEV感染。除了先天免疫和获得性免疫外，许多细胞蛋白还对病毒入侵具有抗病毒活性。人锌指抗病毒蛋白(ZAP)是一种针对多种病毒的细胞限制因子，但其在黄病毒家族中的作用尚不清楚。我们测试了ZAP对三种黄病毒的抗病毒能力，发现日本脑炎病毒(JEV)对ZAP敏感，而登革热病毒和寨卡病毒对ZAP耐药。ZAP特异性靶向JEV病毒RNA，诱导翻译抑制和RNA降解。我们的发现突出了ZAP介导的抗JEV机制，并将ZAP的抗病毒谱扩展到包括黄病毒属的一个成员。
CCCH-type zinc-finger antiviral protein (ZAP) is a host factor that restricts the infection of many viruses mainly through RNA degradation, translation inhibition and innate immune responses. So far, only one flavivirus, yellow fever virus, has been reported to be ZAP-resistant. Here, we investigated the antiviral potential of human ZAP (isoform ZAP-L and ZAP-S) against three flaviviruses, Japanese encephalitis virus (JEV), dengue virus (DENV) and Zika virus (ZIKV). Infection of JEV but not DENV or ZIKV was blocked by ZAP overexpression, and depletion of endogenous ZAP enhanced JEV replication. ZAP hampered JEV translation and targeted viral RNA for 3′-5′ RNA exosome-mediated degradation. The zinc-finger motifs of ZAP were essential for RNA targeting and anti-JEV activity. JEV 3′-UTR, especially in the region with dumbbell structures and high content of CG dinucleotide, was mapped to bind ZAP and confer sensitivity to ZAP. In summary, we identified JEV as the first ZAP-sensitive flavivirus. ZAP may act as an intrinsic antiviral factor through specific RNA binding to fight against JEV infection. In addition to innate and adaptive immunities, many cellular proteins also exert antiviral activity against viral invasion. Human zinc-finger antiviral protein (ZAP) is a cellular restriction factor against many viruses but its role with regard to the flavivirus family is largely unknown. We tested the antiviral potential of ZAP against three flaviviruses and found that Japanese encephalitis virus (JEV) was ZAP-sensitive, while dengue virus and Zika virus were ZAP-resistant. ZAP specifically targets JEV viral RNA and induces translation repression and RNA degradation. Our findings highlight the ZAP-mediated anti-JEV mechanisms and extend the antiviral spectrum of ZAP to include a member of the Flavivirus genus.
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