Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation
Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation
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DOI：
10.1128/jvi.76.22.11476-11483.2002
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发表时间：
2002-11-01
影响因子：
5.4
通讯作者：
Horvath, CM
中科院分区：
文献类型：
--
作者：
Rodriguez, JJ;Parisien, JP;Horvath, CM
对最近在东南亚暴发的致命性脑炎的特征分析确定，病原体是一种以前未被识别的副粘病毒科的包膜负链RNA病毒，即尼帕病毒。将尼帕病毒与这一家族联系起来的一个特征是一个保守的富含半胱氨酸的结构域，这是副粘病毒V蛋白的标志。其他副粘病毒物种的V蛋白通过诱导IFN应答转录因子STAT1或STAT2的蛋白酶体降解，与逃避宿主细胞干扰素（IFN）信号转导和随后的抗病毒应答有关。在这里，我们证明尼帕病毒V蛋白通过直接抑制STAT蛋白功能的独特机制逃避IFN。尼帕病毒V型蛋白与其他副粘病毒V型蛋白的不同之处在于其亚细胞分布，而不是其抑制细胞干扰素反应的能力。尼帕病毒V蛋白不诱导STAT降解，而是通过与STAT1和STAT2形成高分子量复合物来抑制IFN反应。我们证明尼帕病毒V蛋白通过依赖crm1的机制在细胞质中积累，在稳态下改变STAT蛋白的亚细胞分布，并阻止ifn刺激的STAT再分布。与复合物的形成一致，STAT蛋白酪氨酸磷酸化在表达尼帕病毒V蛋白的细胞中受到抑制。因此，尼帕病毒V蛋白有效地阻止STAT1和STAT2核易位以响应IFN，抑制细胞对IFN- α和IFN- γ的反应。
Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V proteins. The V proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V protein escapes IFN by a distinct mechanism involving direct inhibition of STAT protein function. Nipah virus V protein differs from other paramyxovirus V proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT protein subcellular distribution in the steady state, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V protein. As a result, Nipah virus V protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-alpha and IFN-gamma.