Norovirus infection results in assembly of virus-specific G3BP1 granules and evasion of eIF2a signaling
Norovirus infection results in assembly of virus-specific G3BP1 granules and evasion of eIF2a signaling
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诺如病毒感染导致病毒特异性 G3BP1 颗粒组装并逃避 eIF2a 信号传导
DOI：
10.1101/490318
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Brocard M
中科院分区：
文献类型：
--
作者：
Brocard M
在病毒感染期间，RNA复制中间体或病毒蛋白质的积累对宿主细胞施加主要压力。作为回应，细胞应激途径可以通过关闭病毒所依赖的蛋白质合成机制，并触发mRNA积累到应激颗粒中，以限制能量和营养物质的使用，从而迅速施加防御机制。由于这威胁到病毒基因的表达，病毒需要避开这些途径来繁殖。人类诺如病毒是全球胃肠炎爆发的原因。以前，我们表明，鼠诺如病毒（MNV）调节真核起始因子（eIFs）的活性。在这里，我们研究了MNV如何与控制翻译和应激颗粒积累的eIF2α信号轴相互作用。我们发现，虽然MNV感染抑制宿主细胞的翻译，它的结果在组装的病毒特异性颗粒，而不是应力颗粒。进一步的机制分析表明，eIF2α信号转导与翻译停滞是解耦的。此外，RNA结合蛋白G3BP1与病毒因子的相互作用以及其细胞相互作用伙伴的重新分配可以解释诺如病毒逃避应激颗粒组装。这些结果确定了诺如病毒通过操纵宿主应激反应来确保有效复制传播的新策略。
During viral infection, the accumulation of RNA replication intermediates or viral proteins imposes major stress on the host cell. In response, cellular stress pathways can rapidly impose defence mechanisms by shutting off the protein synthesis machinery, which viruses depend on, and triggering the accumulation of mRNAs into stress granules to limit the use of energy and nutrients. Because this threatens viral gene expression, viruses need to evade these pathways to propagate. Human norovirus is responsible for gastroenteritis outbreaks worldwide. Previously we showed that murine norovirus (MNV) regulates the activity of eukaryotic initiation factors (eIFs). Here we examined how MNV interacts with the eIF2α signaling axis controlling translation and stress granules accumulation. We show that while MNV infection represses host cell translation, it results in the assembly of virus-specific granules rather than stress granules. Further mechanistic analyses revealed that eIF2α signaling is uncoupled from translational stalling. Moreover the interaction of the RNA-binding protein G3BP1 with viral factors together with a redistribution of its cellular interacting partners could explain norovirus evasion of stress granules assembly. These results identify novel strategies by which norovirus ensure efficient replication propagation by manipulating the host stress response.