West Nile Virus Differentially Modulates the Unfolded Protein Response To Facilitate Replication and Immune Evasion
West Nile Virus Differentially Modulates the Unfolded Protein Response To Facilitate Replication and Immune Evasion
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DOI：
10.1128/jvi.02050-10
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发表时间：
2011-03-01
影响因子：
5.4
通讯作者：
Mackenzie, Jason M.
中科院分区：
文献类型：
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作者：
Ambrose, Rebecca L.;Mackenzie, Jason M.
为了在细胞内生存，病毒必须具备操纵各种细胞反应的能力，包括代谢和生物合成途径。未折叠蛋白反应（UPR）由各种外部和内部刺激诱导，包括在内质网（ER）中错误折叠蛋白的积累。我们之前的研究表明，黄病毒西尼罗河病毒株库京病毒（WNVKUN）的复制和组装与内质网密切相关。因此，我们试图确定在WNVKUN感染过程中是否诱导了UPR。WNVKUN在复制过程中诱导UPR信号传导，且与复制高峰相协调。有趣的是，信号传导偏向于该反应的ATF6/IRE - 1分支，Xbp - 1激活水平较高，但真核翻译起始因子2α磷酸化及下游转录可忽略不计。我们表明，PERK介导的反应可能部分调节复制，因为外部UPR刺激对早期复制事件有限制作用，并且缺乏PERK的细胞表现出复制增加和病毒释放增多。重要的是，我们表明WNVKUN的疏水性非结构蛋白NS4A和NS4B是UPR的强效诱导剂，它们在抑制α干扰素（IFN - α）诱导的Jak - STAT信号传导方面表现出高度相关性。依次去除NS4A的跨膜结构域表明，降低疏水性会减弱UPR信号传导并恢复IFN - α介导的激活。总体而言，这些结果表明WNVKUN能够刺激UPR以促进复制，并且由疏水性WNVKUN蛋白调节的一般性内质网应激反应的诱导能够增强对抗病毒信号通路的抑制。
For intracellular survival it is imperative that viruses have the capacity to manipulate various cellular responses, including metabolic and biosynthetic pathways. The unfolded protein response (UPR) is induced by various external and internal stimuli, including the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Our previous studies have indicated that the replication and assembly of the flavivirus West Nile virus strain Kunjin virus (WNVKUN) is intimately associated with the ER. Thus, we sought to determine whether the UPR was induced during WNVKUN infection. WNVKUN induces UPR signaling during replication, which is coordinated with peak replication. Interestingly, signaling is biased toward the ATF6/IRE-1 arm of the response, with high levels of Xbp-1 activation but negligible eukaryotic translation initiation factor 2 alpha phosphorylation and downstream transcription. We show that the PERK-mediated response may partially regulate replication, since external UPR stimulation had a limiting effect on early replication events and cells deficient for PERK demonstrated increased replication and virus release. Significantly, we show that the WNVKUN hydrophobic nonstructural proteins NS4A and NS4B are potent inducers of the UPR, which displayed a high correlation in inhibiting Jak-STAT signaling in response to alpha interferon (IFN-alpha). Sequential removal of the transmembrane domains of NS4A showed that reducing hydrophobicity decreased UPR signaling and restored IFN-alpha-mediated activation. Overall, these results suggest that WNVKUN can stimulate the UPR to facilitate replication and that the induction of a general ER stress response, regulated by hydrophobic WNVKUN proteins, can potentiate the inhibition of the antiviral signaling pathway.