Equine Myxovirus Resistance Protein 2 Restricts Lentiviral Replication by Blocking Nuclear Uptake of Capsid Protein.
Equine Myxovirus Resistance Protein 2 Restricts Lentiviral Replication by Blocking Nuclear Uptake of Capsid Protein.
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DOI：
10.1128/jvi.00499-18
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发表时间：
2018-09-15
影响因子：
5.4
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Ji S;Na L;Ren H;Wang Y;Wang X
先前的研究表明，Mx2s的抗病毒能力仅限于灵长类动物，尤其是人类。EIAV已被证明对人类MxB的限制不敏感。这里，我们描述马的Mx2函数。该蛋白在抑制EIAV、HIV-1和siv中起重要作用。eqMx2的抗病毒活性取决于其亚细胞位置和衣壳结合能力。我们的研究结果表明，在病毒感染后，eqMx2改变其原始的细胞质位置并在核膜上积累，在那里它与病毒衣壳结合并阻止逆转录的原病毒dna进入核。相比之下，huMxB不与EIAV衣壳结合，没有EIAV限制作用。这些研究扩大了我们对马Mx2蛋白功能的理解。人类黏液病毒抗性蛋白2 （huMxB）已被证明是一种决定性的I型干扰素（IFN）诱导的宿主因子，参与抑制人类免疫缺陷病毒1型（HIV-1）以及许多其他灵长类慢病毒。这种阻断发生在病毒RNA逆转录之后，在整合到宿主DNA之前，这与蛋白质结合病毒衣壳的能力密切相关。迄今为止，来自非灵长类动物的Mx2s没有显示出抑制HIV-1的能力。在这项研究中，我们检测了马Mx2 （eqMx2）对马传染性贫血病毒（EIAV）和HIV-1的限制性作用，并探讨了其特异性功能的可能机制。我们证明了IFN-α/β上调马单核细胞源性巨噬细胞（emdm）中eqMx2的表达。过表达eqMx2可显著抑制EIAV、HIV-1和猿猴免疫缺陷病毒（SIVs）的复制，但对小鼠白血病病毒（MLV）的复制无抑制作用。eqMx2转录的敲低减弱了I型干扰素对EIAV复制的抑制作用。有趣的是，免疫荧光分析的数据表明，病毒感染后，eqMx2的亚细胞定位发生了变化，从分散在细胞质中到积聚在核膜上。此外，eqMx2通过与病毒衣壳结合来阻断原病毒基因组的核摄取。n端截断的eqMx2突变体失去了与病毒衣壳结合的能力，也失去了对慢病毒的限制性作用。这些结果提高了我们对非灵长类动物中Mx2蛋白的理解。先前的研究表明，Mx2s的抗病毒能力仅限于灵长类动物，尤其是人类。EIAV已被证明对人类MxB的限制不敏感。这里，我们描述马的Mx2函数。该蛋白在抑制EIAV、HIV-1和siv中起重要作用。eqMx2的抗病毒活性取决于其亚细胞位置和衣壳结合能力。我们的研究结果表明，在病毒感染后，eqMx2改变其原始的细胞质位置并在核膜上积累，在那里它与病毒衣壳结合并阻止逆转录的原病毒dna进入核。相比之下，huMxB不与EIAV衣壳结合，没有EIAV限制作用。这些研究扩大了我们对马Mx2蛋白功能的理解。
Previous research has shown that the antiviral ability of Mx2s is confined to primates, particularly humans. EIAV has been shown to be insensitive to restriction by human MxB. Here, we describe the function of equine Mx2. This protein plays an important role in the suppression of EIAV, HIV-1, and SIVs. The antiviral activity of eqMx2 depends on its subcellular location as well as its capsid binding capacity. Our results showed that following viral infection, eqMx2 changes its original cytoplasmic location and accumulates at the nuclear envelope, where it binds to the viral capsid and blocks the nuclear entry of reverse-transcribed proviral DNAs. In contrast, huMxB does not bind to the EIAV capsid and shows no EIAV restriction effect. These studies expand our understanding of the function of the equine Mx2 protein. Human myxovirus resistance protein 2 (huMxB) has been shown to be a determinant type I interferon (IFN)-induced host factor involved in the inhibition of human immunodeficiency virus type 1 (HIV-1) as well as many other primate lentiviruses. This blocking occurs after the reverse transcription of viral RNA and ahead of integration into the host DNA, which is closely connected to the ability of the protein to bind the viral capsid. To date, Mx2s derived from nonprimate animals have shown no capacity for HIV-1 suppression. In this study, we examined the restrictive effect of equine Mx2 (eqMx2) on both equine infectious anemia virus (EIAV) and HIV-1 and investigated possible mechanisms for its specific function. We demonstrated that IFN-α/β upregulates the expression of eqMx2 in equine monocyte-derived macrophages (eMDMs). The overexpression of eqMx2 significantly suppresses the replication of EIAV, HIV-1, and simian immunodeficiency viruses (SIVs) but not that of murine leukemia virus (MLV). The knockdown of eqMx2 transcription weakens the inhibition of EIAV replication by type I interferon. Interestingly, data from immunofluorescence assays suggest that the subcellular localization of eqMx2 changes following virus infection, from being dispersed in the cytoplasm to being accumulated at the nuclear envelope. Furthermore, eqMx2 blocks the nuclear uptake of the proviral genome by binding to the viral capsid. The N-terminally truncated mutant of eqMx2 lost the ability to bind the viral capsid as well as the restriction effect for lentiviruses. These results improve our understanding of the Mx2 protein in nonprimate animals. IMPORTANCE Previous research has shown that the antiviral ability of Mx2s is confined to primates, particularly humans. EIAV has been shown to be insensitive to restriction by human MxB. Here, we describe the function of equine Mx2. This protein plays an important role in the suppression of EIAV, HIV-1, and SIVs. The antiviral activity of eqMx2 depends on its subcellular location as well as its capsid binding capacity. Our results showed that following viral infection, eqMx2 changes its original cytoplasmic location and accumulates at the nuclear envelope, where it binds to the viral capsid and blocks the nuclear entry of reverse-transcribed proviral DNAs. In contrast, huMxB does not bind to the EIAV capsid and shows no EIAV restriction effect. These studies expand our understanding of the function of the equine Mx2 protein.