Vaccinia virus blocks gamma interferon signal transduction: Viral VH1 phosphatase reverses Stat1 activation
Vaccinia virus blocks gamma interferon signal transduction: Viral VH1 phosphatase reverses Stat1 activation
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DOI：
10.1128/jvi.75.7.3185-3196.2001
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发表时间：
2001-04-01
影响因子：
5.4
通讯作者：
Lewis, JA
中科院分区：
文献类型：
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作者：
Najarro, P;Traktman, P;Lewis, JA
我们分析了牛痘病毒（VV）对γ干扰素（ifn - γ）信号转导的影响，在用ifn - γ治疗前2小时感染VV的细胞可抑制Stat1的磷酸化和核易位，从而阻断通常由ifn - γ诱导的mrna的积累，而ifn - γ通路中其他蛋白的磷酸化不受影响，其他配体受体系统对Stat1的激活也被VV阻断。Stat1激活的阻断是剂量依赖性的，尽管不需要病毒蛋白合成，但似乎需要病毒核的进入和剥膜来阻断磷酸化Stat1的积累。这些结果表明，病毒粒子成分负责这种效果。VV病毒粒子含有一种磷酸酶（VH1），它对磷酸酶抑制剂Na3VO4敏感，但对冈田酸不敏感。添加Na3VO4而不是冈田酸可以恢复vv感染细胞中正常的Stat1磷酸化水平。此外，含有低水平VH1的病毒粒子无法阻断ifn - γ信号通路。体外研究表明，磷酸酶可以结合并使Stat1去磷酸化，这表明该转录因子可能是VH1的底物。我们的研究结果揭示了VH1通过病毒磷酸酶VH1的去磷酸化活性阻断ifn - γ信号级联来干扰宿主免疫应答的新机制。
We have analyzed the effects of vaccinia virus (VV) on gamma interferon (IFN-gamma) signal transduction, Infection of cells with VV 1 to 2 h prior to treatment with IFN-gamma inhibits phosphorylation and nuclear translocation of Stat1 and consequently blocks accumulation of mRNAs normally induced by IFN-gamma, While phosphorylation of other proteins in the IFN-gamma pathway was not affected, activation of Stat1 by other ligand-receptor systems was also blocked by VV, This block of Stat1 activation was dose dependent, and although viral protein synthesis was not required, entry and uncoating of viral cores appear to be needed to block the accumulation of phosphorylated Stat1, These results suggest that a virion component is responsible for the effect. VV virions contain a phosphatase (VH1) that is sensitive to the phosphatase inhibitor Na3VO4 but not to okadaic acid. Addition of Na3VO4 but not okadaic acid restored normal Stat1 phosphorylation levels in VV-infected cells. Moreover, virions containing reduced levels of VH1 were unable to block the IFN-gamma signaling pathway. In vitro studies show that the phosphatase can bind and dephosphorylate Stat1, indicating that this transcription factor can be a substrate for VH1, Our results reveal a novel mechanism by which VV interferes with the onset of host immune responses by blocking the IFN-gamma signal cascade through the dephosphorylating activity of the viral phosphatase VH1.