Inhibition of interferon-mediated antiviral activity by murine gammaherpesvirus 68 latency-associated M2 protein
Inhibition of interferon-mediated antiviral activity by murine gammaherpesvirus 68 latency-associated M2 protein
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DOI：
10.1128/jvi.78.22.12416-12427.2004
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发表时间：
2004-11-01
影响因子：
5.4
通讯作者：
Jung, JU
中科院分区：
文献类型：
--
作者：
Liang, XZ;Shin, YC;Jung, JU
病毒感染后，宿主免疫系统的主要防御是激活干扰素 (IFN) 介导的抗病毒途径。为了完成其生命周期，作为必需细胞内寄生虫的病毒必须调节宿主干扰素介导的免疫反应。鼠伽马疱疹病毒 68 (gammaHV68) 可感染多种细胞类型并在小鼠体内建立潜伏感染。在这里，我们证明了 gammaHV68 潜伏相关 M2 蛋白具有细胞类型依赖性定位模式：M2 存在于淋巴细胞的细胞质和质膜中，而它主要存在于上皮细胞和成纤维细胞的细胞核中。突变分析表明，M2 内部带正电荷的氨基酸是其在成纤维细胞中核定位所必需的。 M2 复合物的纯化表明，M2 通过其中心带正电荷的区域与细胞 p32 酸性蛋白特异性相互作用，并且这种相互作用将细胞 p32 蛋白招募到成纤维细胞的细胞核中。无论其定位如何，M2 表达都能有效诱导 A20 B 淋巴细胞和 NIH 3T3 成纤维细胞中 STAT1 和/或 STAT2 的下调，从而抑制 IFN-α/β 和 IFN-γ 介导的转录激活。最后，M2 与 p32 蛋白的相互作用似乎有助于其抑制 IFN 介导的转录激活的能力。这些结果表明，gammaHV68 含有潜伏期相关的 M2 基因，该基因拮抗 IFN 介导的宿主先天免疫，因此可能在受感染动物病毒潜伏期的建立和维持中发挥重要作用。
Upon viral infection, the major defense mounted by the host immune system is the activation of the interferon (IFN)-mediated antiviral pathway. In order to complete their life cycle, viruses that are obligatory intracellular parasites must modulate the host IFN-mediated immune response. Murine gammaherpesvirus 68 (gammaHV68) infects a wide range of cell types and establishes latent infections in mice. Here we demonstrate that the gammaHV68 latency-associated M2 protein has a cell-type-dependent localization pattern: M2 is present in the cytoplasm and plasma membrane in lymphocytes, whereas it is present primarily in the nucleus in epithelial and fibroblast cells. A mutational analysis indicated that the internal positively charged amino acids of M2 are required for its nuclear localization in fibroblasts. Purification of the M2 complex showed that M2 specifically interacts with the cellular p32 acidic protein through its central positively charged region and that this interaction recruits the cellular p32 protein to the nucleus in fibroblasts. Regardless of its localization, M2 expression effectively induced the downregulation of STAT1 and/or STAT2 in both A20 B lymphocytes and NIH 3T3 fibroblasts, resulting in the inhibition of IFN-alpha/beta- and IFN-gamma-mediated transcriptional activation. Finally, the M2 interaction with the p32 protein appeared to contribute to its ability to inhibit IFN-mediated transcriptional activation. These results indicate that gammaHV68 harbors a latency-associated M2 gene that antagonizes IFN-mediated host innate immunity and thus could play an important role in the establishment and maintenance of viral latency in infected animals.