Enterovirus 3A facilitates viral replication by promoting PI4KB-ACBD3 interaction.
Enterovirus 3A facilitates viral replication by promoting PI4KB-ACBD3 interaction.
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肠道病毒 3A 通过促进 PI4KB-ACBD3 相互作用来促进病毒复制。
DOI：
10.1128/jvi.00791-17
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Jianwei Wang
中科院分区：
文献类型：
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作者：
Xia Xiao;Xiaobo Lei;Zhenzhen Zhang;Yijie Ma;Jianli Qi;Chao Wu;Yan Xiao;Li Li;Bin He;Jianwei Wang
与其他肠道病毒一样，肠病毒71型依赖于磷脂酰肌醇4-激酶IIIRNA(PI4Kb)进行基因组β复制。然而，PI4KB如何被招募到EV71的基因组复制位点仍然是个谜。最近，我们报道了EV71病毒复制需要一个宿主因子ACBD3，它与病毒3A蛋白相互作用。在这里，我们证明了ACBD3是PI4KB招募到RNA复制位点所必需的。病毒3A或EV71感染的过表达刺激PI4KB和ACBD3的相互作用。一直以来，EV71感染诱导磷脂酰肌醇-4-磷酸(PI4P)的产生。此外，PI4KB、ACBD3和3A都定位于病毒RNA复制位点。相应地，小干扰RNA(SiRNA)耗尽PI4KB或ACBD3会导致EV71感染后PI4P的产生减少。3A中的I44A或H54Y替换可阻断PI4KB和ACBD3的刺激。进一步的分析表明，刺激ACBD3-PI4KB的相互作用对肠道病毒68的复制也很重要，但对人鼻病毒16不利。这些结果揭示了肠道病毒的复制机制，涉及选择性地将PI4KB重新招募到RNA复制位点。虽然涉及多个因素，但在很大程度上还不清楚病毒复制是如何控制的。我们发现肠道病毒71的3A蛋白通过与β相互作用招募一种酶，磷脂酰肌醇4-激酶III ACBD3，ACBD3通过产生一种脂类PI4P改变细胞膜。因此，病毒和宿主蛋白形成一个大的复合体，这是复制位点合成RNA所必需的。值得注意的是，PI4KB-ACBD3相互作用也不同地介导了肠道病毒68和鼻病毒16的复制。这些结果为了解肠道病毒复制的分子网络提供了新的见解。
Like other enteroviruses, enterovirus 71 (EV71) relies on phosphatidylinositol 4-kinase IIIβ (PI4KB) for genome RNA replication. However, how PI4KB is recruited to the genome replication sites of EV71 remains elusive. Recently, we reported that a host factor, ACBD3, is needed for EV71 replication by interacting with viral 3A protein. Here, we show that ACBD3 is required for the recruitment of PI4KB to RNA replication sites. Overexpression of viral 3A or EV71 infection stimulates the interaction of PI4KB and ACBD3. Consistently, EV71 infection induces the production of phosphatidylinositol-4-phosphate (PI4P). Furthermore, PI4KB, ACBD3, and 3A are all localized to the viral-RNA replication sites. Accordingly, PI4KB or ACBD3 depletion by small interfering RNA (siRNA) leads to a reduction in PI4P production after EV71 infection. I44A or H54Y substitution in 3A interrupts the stimulation of PI4KB and ACBD3. Further analysis suggests that stimulation of ACBD3-PI4KB interaction is also important for the replication of enterovirus 68 but disadvantageous to human rhinovirus 16. These results reveal a mechanism of enterovirus replication that involves a selective strategy for recruitment of PI4KB to the RNA replication sites.IMPORTANCEEnterovirus 71, like other human enteroviruses, replicates its genome within host cells, where viral proteins efficiently utilize cellular machineries. While multiple factors are involved, it is largely unclear how viral replication is controlled. We show that the 3A protein of enterovirus 71 recruits an enzyme, phosphatidylinositol 4-kinase IIIβ, by interacting with ACBD3, which alters cellular membranes through the production of a lipid, PI4P. Consequently, the viral and host proteins form a large complex that is necessary for RNA synthesis at replication sites. Notably, PI4KB-ACBD3 interaction also differentially mediates the replication of enterovirus 68 and rhinovirus 16. These results provide new insight into the molecular network of enterovirus replication.