Enterovirus D68 infection upregulates SOCS3 expression to inhibit JAK-STAT3 signaling and antagonize the innate interferon response of the host

Yuling Zhang; Leling Xu; Zhe Zhang; Xin Su; Zhiyun Wang; Tao Wang

doi:10.1016/j.virs.2023.08.007

October 2023

Yuling Zhang, Leling Xu, Zhe Zhang, Xin Su, Zhiyun Wang and Tao Wang. Enterovirus D68 infection upregulates SOCS3 expression to inhibit JAK-STAT3 signaling and antagonize the innate interferon response of the host[J]. Virologica Sinica, 2023, 38(5): 755-766. doi: 10.1016/j.virs.2023.08.007

Citation: Yuling Zhang, Leling Xu, Zhe Zhang, Xin Su, Zhiyun Wang, Tao Wang. Enterovirus D68 infection upregulates SOCS3 expression to inhibit JAK-STAT3 signaling and antagonize the innate interferon response of the host .VIROLOGICA SINICA, 2023, 38(5) : 755-766. http://dx.doi.org/10.1016/j.virs.2023.08.007

肠道病毒D68感染会上调SOCS3的表达，从而抑制JAK-STAT3信号传导并拮抗宿主的先天干扰素反应

张玉玲 ^a ,
徐乐灵 ^a ,
张哲 ^a ,
苏鑫 ^a ,
王志云 ^b,, ,
王涛 ^a,c,,

a. 天津大学生命科学学院, 中国天津, 300072;
b. 天津大学环境科学与工程学院, 中国天津, 300072;
c. 天津市生物大分子结构功能与应用重点实验室, 中国天津, 300072

通讯作者： 王志云, zhiyun_wang@tju.edu.cn; 王涛, wangtaobio@tju.edu.cn
收稿日期： 2023-03-09
录用日期： 2023-08-25

摘要

肠道病毒 D68（EV-D68）可引起呼吸道疾病和急性弛缓性麻痹，对公众健康构成巨大威胁。干扰素是宿主细胞分泌的细胞因子，具有广谱抗病毒作用，可诱导数百种干扰素刺激基因（ISG）的表达。EV-D68 在感染早期会激活 ISG 的表达，但在后期，病毒会抑制 ISG 的表达，这是 EV-D68 进化出的一种拮抗干扰素的策略。在这里，我们探索了一种宿主蛋白--细胞因子信号转导抑制因子 3（SOCS3）--在 EV-D68 感染期间上调并拮抗 I 型干扰素的抗病毒作用。我们随后证明，EV-D68 的结构蛋白上调了 SOCS3 的转录调节因子 RFX7 的表达，导致 SOCS3 表达上调。进一步研究发现，SOCS3 是通过抑制信号转导和激活转录 3（STAT3）的磷酸化来发挥作用的。SOCS3 的表达抑制了 ISG 的表达，从而抑制了 I 型干扰素的抗病毒作用，促进了 EV-D68 的转录、蛋白质生成和病毒滴度。值得注意的是，失去激酶抑制区（KIR）结构域的 SOCS3 截短体无法促进 EV-D68 的复制和翻译。基于上述研究，我们设计了一种名为 SOCS3 抑制剂的短肽，它能特异性地结合并抑制 SOCS3 的 KIR 结构域，从而显著降低 EV-D68 的 RNA 和蛋白质水平。总之，我们的研究结果证明了 EV-D68 抑制 ISG 转录和拮抗宿主 I 型干扰素抗病毒反应的新机制。
- 肠病毒D68（EV-D68）
- , 干扰素
- , ISG
- , SOCS3
- , STAT3

Enterovirus D68 infection upregulates SOCS3 expression to inhibit JAK-STAT3 signaling and antagonize the innate interferon response of the host

Yuling Zhang ^a ,
Leling Xu ^a ,
Zhe Zhang ^a ,
Xin Su ^a ,
Zhiyun Wang ^b,, ,
Tao Wang ^a,c,,

a. School of Life Sciences, Tianjin University, Tianjin, 300072, China;
b. School of Environmental Science and Engineering, Tianjin University, Tianjin, 300072, China;
c. Institute of Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Tianjin, 300072, China

Corresponding author: Zhiyun Wang, zhiyun_wang@tju.edu.cn Tao Wang, wangtaobio@tju.edu.cn
Received Date: 09 March 2023
Accepted Date: 25 August 2023

Abstract

Enterovirus D68 (EV-D68) can cause respiratory diseases and acute flaccid paralysis, posing a great threat to public health. Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects, inducing the expression of hundreds of interferon-stimulated genes (ISGs). EV-D68 activates ISG expression early in infection, but at a later stage, the virus suppresses ISG expression, a strategy evolved by EV-D68 to antagonize interferons. Here, we explore a host protein, suppressor of cytokine signaling 3 (SOCS3), is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon. We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7, a transcriptional regulator of SOCS3, leading to the upregulation of SOCS3 expression. Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). The expression of SOCS3 inhibited the expression of ISG, thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription, protein production, and viral titer. Notably, a truncated SOCS3, generated by deleting the kinase inhibitory region (KIR) domain, failed to promote replication and translation of EV-D68. Based on the above studies, we designed a short peptide named SOCS3 inhibitor, which can specifically bind and inhibit the KIR structural domain of SOCS3, significantly reducing the RNA and protein levels of EV-D68. In summary, our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.
- Enterovirus D68 (EV-D68)
- , Interferon
- , ISG
- , SOCS3
- , STAT3

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10.1016j.virs.2023.08.007-ESM.doc