Dengue Non-structural Protein 5 Polymerase Complexes With Promyelocytic Leukemia Protein (PML) Isoforms III and IV to Disrupt PML-Nuclear Bodies in Infected Cells
Dengue Non-structural Protein 5 Polymerase Complexes With Promyelocytic Leukemia Protein (PML) Isoforms III and IV to Disrupt PML-Nuclear Bodies in Infected Cells
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DOI：
10.3389/fcimb.2019.00284
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发表时间：
2019-08-13
影响因子：
5.7
通讯作者：
Garcia, Cybele
中科院分区：
文献类型：
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作者：
Giovannoni, Federico;Fatima Ladelf, Maria;Garcia, Cybele
登革病毒（DENV）威胁着世界上近70%的人口，目前没有治疗方法。登革病毒病（登革出血热/登革休克综合征）的严重、潜在致命形式与作为宿主抗病毒应答的一部分引起的高水平细胞因子的产生相关，尽管分子机制尚未完全阐明。我们先前表明，DENV血清型2（DENV 2）感染破坏了感染细胞中病毒蛋白翻译后的早幼粒细胞白血病（PML）基因产物核体（PML-NB）。除了在形成PML-NB中作为成核剂发挥关键作用外，PML还具有抗多种病毒的抗病毒活性，包括DENV。本研究建立在这项工作的基础上，首次显示所有四种DENV血清型都引起PML-NB分解。重要的是，我们第一次表明，在DENV的核定位蛋白中，DENV非结构蛋白（NS）5聚合酶单独足以引起PML-NB分解，部分是通过与PML亚型III和IV复合，而不是其他PML亚型或其他PML-NB组分。结果提出了核定位的NS 5破坏PML-NB有助于DENV抑制宿主抗病毒反应的可能性。
Dengue virus (DENV) threatens almost 70% of the world's population, with no therapeutic currently available. The severe, potentially lethal forms of DENV disease (dengue hemorrhagic fever/dengue shock syndrome) are associated with the production of high level of cytokines, elicited as part of the host antiviral response, although the molecular mechanisms have not been fully elucidated. We previously showed that infection by DENV serotype 2 (DENV2) disrupts promyelocytic leukemia (PML) gene product nuclear bodies (PML-NBs) after viral protein translation in infected cells. Apart from playing a key role as the nucleating agent in forming PML-NBs, PML has antiviral activity against various viruses, including DENV. The present study builds on this work, showing for the first time that all four DENV serotypes elicit PML-NB breakdown. Importantly, we show for the first time that of the nuclear localizing proteins of DENV, DENV non-structural protein (NS) 5 polymerase alone is sufficient to elicit PML-NB disassembly, in part through complexing with PML isoforms III and IV, but not other PML isoforms or other PML-NB components. The results raise the possibility that PML-NB disruption by nuclear localized NS5 contributes to DENV's suppression of the host antiviral response.