Marek’s disease virus inhibits the JAK–STAT signaling pathway to evade the innate immune response

doi:10.1016/j.jia.2024.11.019

Journal of Integrative Agriculture

2026, Vol. 25

Issue (7): 2970-2981 DOI: 10.1016/j.jia.2024.11.019

Animal Science · Veterinary Medicine

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Marek’s disease virus inhibits the JAK–STAT signaling pathway to evade the innate immune response

Tong Zhou¹, Peidong Guo¹, Li Gao¹, Rui Liu¹, Changjun Liu¹, Yanping Zhang¹, Hongyu Cui¹, Xiaole Qi¹, Yongzhen Liu¹, Suyan Wang¹, Yuntong Chen¹, Yulu Duan¹, Xiaomei Wang^{1, 4}, Yulong Gao^1#, Kai Li^{1, 2, 3#}

¹ Avian Immunosuppressive Diseases Division, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China

² Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu 610213, China

³ Chengdu National Agricultural Science and Technology Center, Chengdu 610213, China

⁴ Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou 225009, China

Highlights
● Marek’s disease virus (MDV) reduced interferon-stimulated genes (ISGs) production by inhibiting signal transducer and activator of transcription 1 (STAT1) nuclear translocation.
● Meq reduced interferon-stimulated response element (ISRE) promoter activity and inhibited STAT1 phosphorylation.
● Meq interacted with JAK1 and tyrosine kinase 2 (TYK2) and inhibited JAK1–STAT1 interactions.
● Meq degraded TYK2 via a caspase-mediated pathway.
● Meq-deficient MDV replicated less efficiently than wild-type MDV.

Abstract
References

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摘要

Janus激酶（JAK）-信号转导及转录激活因子（STAT）信号通路通过响应干扰素信号并诱导抗病毒蛋白表达，在天然免疫中发挥着至关重要的作用。马立克氏病病毒（MDV）属于α-疱疹病毒科成员，具有强大的致瘤性和免疫抑制效应。近年来的研究主要集中在MDV的致瘤机制上，而其免疫逃逸机制尚未被完全阐明。在本研究中，我们发现MDV通过抑制STAT1的磷酸化及其核易位，从而减少干扰素刺激基因（ISGs）的产生。利用双荧光素酶报告基因系统，我们筛选出了能够显著抑制干扰素刺激反应元件（ISRE）启动子活性的病毒蛋白。结果显示，Meq蛋白的过表达显著降低了ISRE启动子活性和ISGs的表达；相反，体外和体内实验表明，与野生型MDV相比，Meq缺失型MDV感染能够诱导产生更高水平的ISGs。此外，Meq还能抑制STAT1的磷酸化和核易位。进一步的实验表明，Meq可与JAK1及酪氨酸激酶2（TYK2）发生相互作用，进而阻断JAK1与STAT1之间的相互作用。Meq还通过半胱氨酸蛋白酶（caspase）介导的途径降解TYK2。体外和体内研究均证实，Meq缺失型MDV突变株的复制效率低于野生型MDV。综上所述，这些研究结果表明，Meq通过削弱JAK-STAT信号通路在MDV中发挥免疫抑制作用，从而促进其逃逸天然免疫监视机制。

Abstract

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway plays a crucial role in innate immunity by inducing antiviral proteins in response to interferon signals. Marek’s disease virus (MDV), a member of the alphaherpesvirus family, exerts potent tumorigenic and immunosuppressive effects. Recent studies have primarily focused on the tumorigenic mechanisms of MDV, and the mechanism of immune evasion has not been fully understood. In this study, we showed that MDV reduced the production of interferon-stimulated genes (ISGs) by inhibiting the phosphorylation and nuclear translocation of STAT1. Using a dual-luciferase reporter system, we screened for viral proteins that significantly suppress interferon-stimulated response element (ISRE) promoter activity. Meq overexpression markedly reduced ISRE promoter activity and ISG expression, whereas infection with Meq-deficient MDV induced higher ISG production in vitro and in vivo than infection with wild-type MDV. Meq also inhibited the phosphorylation and nuclear translocation of STAT1. Further experiments showed that Meq interacted with JAK1 and tyrosine kinase 2 (TYK2) and thereby inhibited JAK1–STAT1 interactions. Meq degraded TYK2 via a caspase-mediated pathway. The Meq-deficient MDV mutant replicated less efficiently than the wild-type MDV, both in vitro and in vivo. Collectively, these findings demonstrate that Meq played an immunosuppressive role in MDV by attenuating the JAK–STAT signaling pathway, which facilitated escape from innate immune surveillance mechanisms.

Keywords: Marek’s disease JAK–STAT innate immunity immune evasion interferon-stimulated gene

Received: 26 June 2024 Accepted: 08 October 2024 Online: 12 November 2024

Fund:

This research was supported by grants from the National Natural Science Foundation of China (32270154, U20A2061), the Central Public-interest Scientific Institution Basal Research Fund, China (Y2022QC26), and the China Agricultural Research System (CARS-41-G15).

About author: #Correspondence Yulong Gao, E-mail: gaoyulong@caas.cn; Kai Li, Tel: +86-451-51051694, Fax: +86-451-51997166, E-mail: likai01@caas.cn

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Cite this article:

Tong Zhou, Peidong Guo, Li Gao, Rui Liu, Changjun Liu, Yanping Zhang, Hongyu Cui, Xiaole Qi, Yongzhen Liu, Suyan Wang, Yuntong Chen, Yulu Duan, Xiaomei Wang, Yulong Gao, Kai Li. 2026. Marek’s disease virus inhibits the JAK–STAT signaling pathway to evade the innate immune response. Journal of Integrative Agriculture, 25(7): 2970-2981.

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