IFN-β1b induces OAS3 to inhibit EV71 via IFN-β1b/JAK/STAT1 pathway

Baisong Zheng; Xiaolei Zhou; Li Tian; Jian Wang; Wenyan Zhang

doi:10.1016/j.virs.2022.07.013

October 2022

. doi: 10.1016/j.virs.2022.07.013

Citation: Baisong Zheng, Xiaolei Zhou, Li Tian, Jian Wang, Wenyan Zhang. IFN-β1b induces OAS3 to inhibit EV71 via IFN-β1b/JAK/STAT1 pathway .VIROLOGICA SINICA, 2022, 37(5) : 676-684. http://dx.doi.org/10.1016/j.virs.2022.07.013

IFN-β1b通过IFN-β1b/JAK/STAT1通路诱导OAS3抑制肠道病毒EV71的复制

吉林大学第一医院, 感染性疾病和病原生物学研究中心, 艾滋病与病毒研究所, 器官再生与移植教育部重点实验室

通讯作者： 张文艳, zhangwenyan@jlu.edu.cn
收稿日期： 2022-01-21
录用日期： 2022-07-27

摘要

由肠道病毒71型（EV71）引起的手足口病（HFMD）严重威胁幼儿健康。虽然已有证据表明I型干扰素（IFN-I）可以控制EV71的复制，但关键的下游IFN刺激基因（ISG）仍有待阐明和研究。最近，我们研究也发现作为干扰素-β1b的下游刺激基因之一的2'-5'-寡腺苷酸合成酶3（OAS3）可以被EV71 3C蛋白酶拮抗。在本文中，我们确认OAS3是干扰素-β1b介导的抑制EV71复制的重要因子。OAS3的这一作用依赖于下游组成性RNA酶L（RNase L）的激活。OAS3的2'-5'-寡腺苷酸（2-5A）合成活性缺陷突变体D816A、D818A、D888A和K950A失去了对EV71的抑制作用。其原因是失活的OAS3不能激活下游RNase L。进一步的研究证明，EV71感染可以通过刺激干扰素途径诱导OAS3而不是RNase L的表达。机制方面的研究表明，EV71感染或IFN-β1b处理可以诱导细胞内STAT1而非STAT3的磷酸化。STAT1通过直接结合OAS3启动子的特定区域，启动OAS3的转录。我们的工作阐明了宿主OAS3/RNase L系统对抗EV71复制的免疫调节机制。
- EV71
- , OAS3
- , RNase L
- , IFN-β1b
- , JAK/STAT

IFN-β1b induces OAS3 to inhibit EV71 via IFN-β1b/JAK/STAT1 pathway

Center for Pathogen Biology and Infectious Diseases, Institute of Virology and AIDS Research, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China

Corresponding author: Wenyan Zhang, zhangwenyan@jlu.edu.cn
Received Date: 21 January 2022
Accepted Date: 27 July 2022

Abstract

Enterovirus 71 (EV71) caused hand, foot and mouth disease (HFMD) is a serious threat to the health of young children. Although type I interferon (IFN-I) has been proven to control EV71 replication, the key downstream IFN-stimulated gene (ISG) remains to be clarified and investigated. Recently, we found that 2'-5'-oligoadenylate synthetases 3 (OAS3), as one of ISG of IFN-β1b, was antagonized by EV71 3C protein. Here, we confirm that OAS3 is the major determinant of IFN-β1b-mediated EV71 inhibition, which depends on the downstream constitutive RNase L activation. 2'-5'-oligoadenylate (2-5A) synthesis activity deficient mutations of OAS3 D816A, D818A, D888A, and K950A lost resistance to EV71 because they could not activate downstream RNase L. Further investigation proved that EV71 infection induced OAS3 but not RNase L expression by IFN pathway. Mechanically, EV71 or IFN-β1b-induced phosphorylation of STAT1, but not STAT3, initiated the transcription of OAS3 by directly binding to the OAS3 promoter. Our works elucidate the immune regulatory mechanism of the host OAS3/RNase L system against EV71 replication.
- Enterovirus 71 (EV71)
- , 2'-5'-oligoadenylate synthetases 3 (OAS3)
- , RNase L
- , IFN-β1b
- , JAK/STAT

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Electronic Supplementary Material

10.1016j.virs.2022.07.013-ESM.docx