Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery.
Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery.
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DOI：
10.1371/journal.ppat.1000493
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Ozato K
中科院分区：
文献类型：
--
作者：
Chang TH;Kubota T;Matsuoka M;Jones S;Bradfute SB;Bray M;Ozato K
埃博拉-扎伊尔病毒对人类具有高度致病性，在非洲的大规模暴发中，病例死亡率接近90%。该病毒在巨噬细胞和树突状细胞(DC)中复制，抑制I型干扰素(IFN)的产生，同时诱导大量促炎细胞因子的释放。虽然病毒VP35蛋白已被证明可抑制干扰素反应，但其阻断干扰素产生的机制尚未完全阐明。我们通过逆转录病毒基因转移在小鼠树突状细胞中表达了来自埃博拉-扎伊尔病毒小鼠适应变种的VP35，并检测了新城疫病毒感染后的干扰素转录和Toll样受体信号转导。我们发现，VP35通过抑制干扰素转录所需的转录因子IRF7的活性来抑制这些刺激后DC中的干扰素转录。通过酵母双杂交筛选和免疫共沉淀实验，我们发现VP35与IRF7、Ubc9和PIAS1相互作用。后两种酶分别是宿主相扑E2酶和E3连接酶。VP35虽然本身不是相扑连接酶，但它增加了PIAS1介导的IRF7的SUMO化，并抑制了干扰素的转录。相反，VP35不干扰NF-κB的激活，而后者是诱导许多促炎细胞因子所必需的。我们的发现表明，埃博拉扎伊尔病毒利用细胞SUMO化机制来发挥其优势，并有助于解释该病毒如何克服宿主的先天防御，导致迅速压倒性感染，产生一种类似暴发性败血症休克的综合征。埃博拉扎伊尔病毒在人类中引起严重出血热，几乎90%的病例是致命的。病毒迅速传播到巨噬细胞和树突状细胞，导致释放高水平的炎性细胞因子，导致休克和出血。埃博拉病毒压倒宿主防御的能力被认为是由于它抑制了I型干扰素(干扰素)反应。众所周知，埃博拉病毒蛋白VP35可以阻断干扰素的反应，但确切的机制尚未确定。我们在小鼠树突状细胞中表达了VP35，发现这些细胞在感染新城疫病毒时不能产生正常的干扰素反应。通过酵母双杂交系统和其他生化实验，我们证明这种阻断是由于一个小的泛素样修饰物(SUMO)蛋白与IRF-7结合而产生的，IRF-7是干扰素基因表达所需的主要细胞因子。然而，这些细胞仍然能够激活NF-κB，这是一种负责释放促炎细胞因子的转录因子。我们的发现提供了第一个病毒劫持宿主相扑系统以破坏天然免疫的例子，并有助于解释埃博拉病毒如何在淋巴组织中迅速传播，导致致命性炎症综合征。
Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs), suppressing production of type I interferons (IFNs) while inducing the release of large quantities of proinflammatory cytokines. Although the viral VP35 protein has been shown to inhibit IFN responses, the mechanism by which it blocks IFN production has not been fully elucidated. We expressed VP35 from a mouse-adapted variant of Ebola Zaire virus in murine DCs by retroviral gene transfer, and tested for IFN transcription upon Newcastle Disease virus (NDV) infection and toll-like receptor signaling. We found that VP35 inhibited IFN transcription in DCs following these stimuli by disabling the activity of IRF7, a transcription factor required for IFN transcription. By yeast two-hybrid screens and coimmunoprecipitation assays, we found that VP35 interacted with IRF7, Ubc9 and PIAS1. The latter two are the host SUMO E2 enzyme and E3 ligase, respectively. VP35, while not itself a SUMO ligase, increased PIAS1-mediated SUMOylation of IRF7, and repressed Ifn transcription. In contrast, VP35 did not interfere with the activation of NF-κB, which is required for induction of many proinflammatory cytokines. Our findings indicate that Ebola Zaire virus exploits the cellular SUMOylation machinery for its advantage and help to explain how the virus overcomes host innate defenses, causing rapidly overwhelming infection to produce a syndrome resembling fulminant septic shock. Ebola Zaire virus causes severe hemorrhagic fever in humans that is fatal in almost 90% of cases. The rapid spread of the virus to macrophages and dendritic cells results in the release of high levels of inflammatory cytokines, causing shock and bleeding. The ability of Ebola virus to overwhelm host defenses is believed to result from its suppression of the type I interferon (IFN) response. The Ebola viral protein VP35 is known to block IFN responses, but the precise mechanisms have not been identified. We expressed VP35 in mouse dendritic cells and found that the cells failed to develop a normal IFN response when infected with Newcastle Disease virus. By a yeast two-hybrid system and other biochemical experiments, we showed that the blockade resulted from the conjugation of a Small Ubiquitin-like Modifier (SUMO) protein to IRF-7, the principal cellular factor required for IFN gene expression. However, the cells were still able to activate NF-κB, a transcription factor responsible for the release of proinflammatory cytokines. Our findings provide a first example where a virus hijacks the host SUMO system to undermine innate immunity, and help to explain how Ebola virus spreads rapidly in lymphoid tissues to cause a lethal inflammatory syndrome.
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