Guo Longjun, Luo Xiaolei, Li Ren, Xu Yunfei, Zhang Jian, Ge Jinying, Bu Zhigao, Feng Li, Wang Yue
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
J Virol. 2016 Aug 26;90(18):8281-92. doi: 10.1128/JVI.01091-16. Print 2016 Sep 15.
Porcine epidemic diarrhea virus (PEDV) is a worldwide-distributed alphacoronavirus, but the pathogenesis of PEDV infection is not fully characterized. During virus infection, type I interferon (IFN) is a key mediator of innate antiviral responses. Most coronaviruses develop some strategy for at least partially circumventing the IFN response by limiting the production of IFN and by delaying the activation of the IFN response. However, the molecular mechanisms by which PEDV antagonizes the antiviral effects of interferon have not been fully characterized. Especially, how PEDV impacts IFN signaling components has yet to be elucidated. In this study, we observed that PEDV was relatively resistant to treatment with type I IFN. Western blot analysis showed that STAT1 expression was markedly reduced in PEDV-infected cells and that this reduction was not due to inhibition of STAT1 transcription. STAT1 downregulation was blocked by a proteasome inhibitor but not by an autophagy inhibitor, strongly implicating the ubiquitin-proteasome targeting degradation system. Since PEDV infection-induced STAT1 degradation was evident in cells pretreated with the general tyrosine kinase inhibitor, we conclude that STAT1 degradation is independent of the IFN signaling pathway. Furthermore, we report that PEDV-induced STAT1 degradation inhibits IFN-α signal transduction pathways. Pharmacological inhibition of STAT1 degradation rescued the ability of the host to suppress virus replication. Collectively, these data show that PEDV is capable of subverting the type I interferon response by inducing STAT1 degradation.
In this study, we show that PEDV is resistant to the antiviral effect of IFN. The molecular mechanism is the degradation of STAT1 by PEDV infection in a proteasome-dependent manner. This PEDV infection-induced STAT1 degradation contributes to PEDV replication. Our findings reveal a new mechanism evolved by PEDV to circumvent the host antiviral response.
猪流行性腹泻病毒（PEDV）是一种在全球范围内分布的甲型冠状病毒，但PEDV感染的发病机制尚未完全明确。在病毒感染过程中，I型干扰素（IFN）是先天性抗病毒反应的关键介质。大多数冠状病毒会通过限制IFN的产生和延迟IFN反应的激活，来制定一些策略至少部分规避IFN反应。然而，PEDV拮抗干扰素抗病毒作用的分子机制尚未完全明确。特别是，PEDV如何影响IFN信号传导成分尚待阐明。在本研究中，我们观察到PEDV对I型干扰素治疗相对耐药。蛋白质印迹分析表明，在PEDV感染的细胞中STAT1表达明显降低，且这种降低并非由于STAT1转录受到抑制。蛋白酶体抑制剂可阻断STAT1的下调，但自噬抑制剂则不能，这强烈提示泛素-蛋白酶体靶向降解系统参与其中。由于在用一般酪氨酸激酶抑制剂预处理的细胞中，PEDV感染诱导的STAT1降解很明显，我们得出结论，STAT1降解独立于IFN信号通路。此外，我们报告PEDV诱导的STAT1降解抑制IFN-α信号转导通路。对STAT1降解的药理学抑制挽救了宿主抑制病毒复制的能力。总体而言，这些数据表明PEDV能够通过诱导STAT1降解来颠覆I型干扰素反应。
在本研究中，我们表明PEDV对IFN的抗病毒作用具有抗性。分子机制是PEDV感染以蛋白酶体依赖的方式降解STAT1。这种PEDV感染诱导的STAT1降解有助于PEDV复制。我们的发现揭示了PEDV进化出的一种规避宿主抗病毒反应的新机制。
