Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication
Host cytoskeletal vimentin serves as a structural organizer and an RNA-binding protein regulator to facilitate Zika viral replication
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DOI：
10.1101/2021.04.25.441301
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发表时间：
2021-04
影响因子：
11.1
通讯作者：
Yue Zhang;Shuangshuang Zhao;Yian Li;F. Feng;Min Li;Yanhong Xue;Jie Cui;Tao Xu;Xia Jin;Yaming Jiu
中科院分区：
文献类型：
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作者：
Yue Zhang;Shuangshuang Zhao;Yian Li;F. Feng;Min Li;Yanhong Xue;Jie Cui;Tao Xu;Xia Jin;Yaming Jiu
寨卡病毒（ZIKV）是寨卡病毒的一种常见类型。波形蛋白网络重组以包围复制复合体。波形蛋白的消耗导致病毒蛋白的剧烈分离和随后的缺陷性感染，表明其作为“组织者”的功能，确保了高复制效率的所有必要因素的浓度。通过组学分析，我们证明了波形蛋白在感染过程中也是一种主导RNA结合蛋白的“调节剂”。这两种作用相互补充，以形成波形蛋白在调节ZIKV感染中的综合观点。总的来说，我们的研究填补了我们对中间丝的细胞功能以及结构支持的长期知识空白，并为ZIKV治疗提供了潜在的靶点。新出现的微生物感染，如寨卡病毒（ZIKV），对人类健康构成越来越大的威胁。对ZIKV复制的研究已经揭示了复制复合物（RC）的构建，但细胞骨架在该过程中的作用在很大程度上是未知的。在这里，我们研究了细胞骨架中间丝蛋白波形蛋白在ZIKV感染的生命周期中的功能。利用先进的成像技术，我们发现波形蛋白丝在病毒蛋白质合成时经历剧烈的重组，形成一个包围和浓缩RC的核周笼状结构。波形蛋白的遗传去除明显破坏了RC的完整性，并导致病毒蛋白的亚细胞分散。这导致减少病毒基因组复制、病毒蛋白质产生和感染性病毒体的释放，而不中断病毒结合和进入。此外，质谱和RNA测序筛选鉴定了波形蛋白和数百种内质网（ER）驻留RNA结合蛋白之间的相互作用和相互作用。其中，核糖体受体结合蛋白1的胞质区域（一种直接结合病毒RNA的ER跨膜蛋白）与波形蛋白相互作用并受波形蛋白调节，从而调节ZIKV复制。总之，我们工作中的数据揭示了波形蛋白作为RC完整性的结构元件和ZIKV感染期间RNA结合调节中心的双重作用，从而揭示了寨卡病毒和宿主细胞之间的相互作用。
Significance We discovered a dual role of vimentin underlying Zika virus (ZIKV) replication. The vimentin network reorganizes to surround the replication complex. Depletion of vimentin resulted in drastic segregation of viral proteins and subsequent defective infection, indicating its function as an “organizer” that ensures the concentration of all necessary factors for high replication efficacy. With omics analysis, we prove that vimentin also functions as a “regulator” that dominates RNA-binding proteins during infection. These two roles complement one another to make an integrated view of vimentin in regulating ZIKV infection. Collectively, our study fills the long-term gap in our knowledge of the cellular function of intermediate filaments in addition to structural support and provides a potential target for ZIKV therapy. Emerging microbe infections, such as Zika virus (ZIKV), pose an increasing threat to human health. Investigations on ZIKV replication have revealed the construction of replication complexes (RCs), but the role of cytoskeleton in this process is largely unknown. Here, we investigated the function of cytoskeletal intermediate filament protein vimentin in the life cycle of ZIKV infection. Using advanced imaging techniques, we uncovered that vimentin filaments undergo drastic reorganization upon viral protein synthesis to form a perinuclear cage-like structure that embraces and concentrates RCs. Genetic removal of vimentin markedly disrupted the integrity of RCs and resulted in fragmented subcellular dispersion of viral proteins. This led to reduced viral genome replication, viral protein production, and release of infectious virions, without interrupting viral binding and entry. Furthermore, mass spectrometry and RNA-sequencing screens identified interactions and interplay between vimentin and hundreds of endoplasmic reticulum (ER)-resident RNA-binding proteins. Among them, the cytoplasmic-region of ribosome receptor binding protein 1, an ER transmembrane protein that directly binds viral RNA, interacted with and was regulated by vimentin, resulting in modulation of ZIKV replication. Together, the data in our work reveal a dual role for vimentin as a structural element for RC integrity and as an RNA-binding-regulating hub during ZIKV infection, thus unveiling a layer of interplay between Zika virus and host cell.