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蜱传脑炎病毒 NS4A 的泛素化拮抗 I 型干扰素刺激的 STAT1/2 信号通路。

Tick-borne encephalitis virus NS4A ubiquitination antagonizes type I interferon-stimulated STAT1/2 signalling pathway.

机构信息

Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou, People's Republic of China.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People's Republic of China.

出版信息

Emerg Microbes Infect. 2020 Dec;9(1):714-726. doi: 10.1080/22221751.2020.1745094.

DOI:10.1080/22221751.2020.1745094
PMID:32196427
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7170394/
Abstract

Tick-borne encephalitis virus (TBEV) accounts for approximately 10,000 annual cases of severe encephalitis in Europe and Asia and causes encephalitis in humans. In this study, we demonstrate TBEV appears to activate the interferon (IFN)-β dependent on RIG-I/MDA5. Both the IFN-β accumulation and the IFN stimulated genes (ISGs) transcription greatly delay. Further studies reveal that TBEV NS4A could block the phosphorylation and dimerization of STAT1/STAT2 to affect type I and II IFN-mediated STAT signalling. Additional data indicate that the residue at K132 of TBEV NS4A could be modified by ubiquitination and this modification is necessary for the interaction of NS4A with STAT1. Dynamic ubiquitination of the NS4 protein during TBEV infection might account for delayed activation of the ISGs. These results define the TBEV NS4A as an antagonist of the IFN response, by demonstrating a correlation between the association and STAT interference. Our findings provide a foundation for further understanding how TBEV evade innate immunity and a potential viral target for intervention.

摘要

蜱传脑炎病毒（TBEV）在欧洲和亚洲每年导致约 10000 例严重脑炎病例，并导致人类脑炎。在这项研究中，我们证明 TBEV 似乎可以激活依赖于 RIG-I/MDA5 的干扰素（IFN）-β。IFN-β 的积累和 IFN 刺激基因（ISGs）的转录都大大延迟。进一步的研究表明，TBEV NS4A 可以阻断 STAT1/STAT2 的磷酸化和二聚化，从而影响 I 型和 II 型 IFN 介导的 STAT 信号转导。额外的数据表明，TBEV NS4A 的 K132 残基可以通过泛素化修饰，这种修饰对于 NS4A 与 STAT1 的相互作用是必需的。在 TBEV 感染期间，NS4 蛋白的动态泛素化可能导致 ISGs 的激活延迟。这些结果通过证明 NS4A 与 STAT 干扰之间的关联，将 TBEV NS4A 定义为 IFN 反应的拮抗剂。我们的研究结果为进一步了解 TBEV 如何逃避先天免疫和作为干预的潜在病毒靶点提供了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/1237377c653b/TEMI_A_1745094_F0008_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/7bf981279d4d/TEMI_A_1745094_F0001_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/a186279314e9/TEMI_A_1745094_F0002_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/8769c05b8620/TEMI_A_1745094_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/f4f56929c4cd/TEMI_A_1745094_F0004_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/3c76f9d67dbe/TEMI_A_1745094_F0005_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/54b5d1ab1f29/TEMI_A_1745094_F0006_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/152bf4a7cc98/TEMI_A_1745094_F0007_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/1237377c653b/TEMI_A_1745094_F0008_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/7bf981279d4d/TEMI_A_1745094_F0001_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/a186279314e9/TEMI_A_1745094_F0002_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/8769c05b8620/TEMI_A_1745094_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/f4f56929c4cd/TEMI_A_1745094_F0004_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/3c76f9d67dbe/TEMI_A_1745094_F0005_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/54b5d1ab1f29/TEMI_A_1745094_F0006_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/152bf4a7cc98/TEMI_A_1745094_F0007_OB.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2745/7170394/1237377c653b/TEMI_A_1745094_F0008_OB.jpg

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