DDX21, a Host Restriction Factor of FMDV IRES-Dependent Translation and Replication.
DDX21, a Host Restriction Factor of FMDV IRES-Dependent Translation and Replication.
复制标题
DDX 21是口蹄疫病毒IRES依赖性翻译和复制的宿主限制因子。
DOI：
10.3390/v13091765
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发表时间：
2021-09-03
期刊：
影响因子：
--
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Abdullah SW;Wu J;Zhang Y;Bai M;Guan J;Liu X;Sun S;Guo H
在细胞中，死亡盒解旋酶（DDXs）的贡献至关重要，没有它，细胞生命是不可能的。核仁解旋酶DDX 21的极其多样的作用，从基本的细胞过程，如细胞生长，核糖体生物合成，蛋白质翻译，蛋白质-蛋白质相互作用，介导和传感转录，基因调控到病毒操纵，引起了我们的注意。我们设计了这个项目来研究病毒-宿主相互作用和病毒的发病机制。采用pulldown试验研究口蹄疫病毒（FMDV）与DDX 21的相关性。通过双荧光素酶、敲低、过表达、qPCR和共聚焦显微镜测定获得对DDX 21-FMDV相互作用的进一步了解。我们的研究结果突出了DDX 21对FMDV的拮抗作用，因为它通过与FMDV IRES结构域2、3和4的结合逐渐抑制FMDV内部核糖体进入位点（IRES）依赖性翻译。为了破坏这种宿主解旋酶拮抗作用，FMDV通过其非结构蛋白2B、2C和3C蛋白酶（3Cpro）降解DDX 21。我们的研究结果表明，DDX 21降解过程中2B和2C过表达和口蹄疫病毒感染通过半胱天冬酶途径;然而，DDX 21降解过程中3Cpro过表达通过溶酶体途径。进一步的研究表明，DDX 21增强干扰素β和白细胞介素-8的产生，以限制病毒复制。总之，我们的研究结果表明，DDX 21是一种新的FMDV IRES反式作用因子，负调控FMDV IRES依赖的翻译和复制。
In cells, the contributions of DEAD-box helicases (DDXs), without which cellular life is impossible, are of utmost importance. The extremely diverse roles of the nucleolar helicase DDX21, ranging from fundamental cellular processes such as cell growth, ribosome biogenesis, protein translation, protein–protein interaction, mediating and sensing transcription, and gene regulation to viral manipulation, drew our attention. We designed this project to study virus–host interactions and viral pathogenesis. A pulldown assay was used to investigate the association between foot-and-mouth disease virus (FMDV) and DDX21. Further insight into the DDX21–FMDV interaction was obtained through dual-luciferase, knockdown, overexpression, qPCR, and confocal microscopy assays. Our results highlight the antagonistic feature of DDX21 against FMDV, as it progressively inhibited FMDV internal ribosome entry site (IRES) -dependent translation through association with FMDV IRES domains 2, 3, and 4. To subvert this host helicase antagonism, FMDV degraded DDX21 through its non-structural proteins 2B, 2C, and 3C protease (3Cpro). Our results suggest that DDX21 is degraded during 2B and 2C overexpression and FMDV infection through the caspase pathway; however, DDX21 is degraded through the lysosomal pathway during 3Cpro overexpression. Further investigation showed that DDX21 enhanced interferon-beta and interleukin-8 production to restrict viral replication. Together, our results demonstrate that DDX21 is a novel FMDV IRES trans-acting factor, which negatively regulates FMDV IRES-dependent translation and replication.
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