Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
United States Department of Agriculture, Agricultural Research Service, Foreign Animal Disease Research Unit, Plum Island Animal Disease Center, Orient, New York, USA.
J Virol. 2019 Jan 4;93(2). doi: 10.1128/JVI.00922-18. Print 2019 Jan 15.
Like other viruses, the picornavirus foot-and-mouth disease virus (FMDV; genus ), one of the most notorious pathogens in the global livestock industry, needs to navigate antiviral host responses to establish an infection. There is substantial insight into how FMDV suppresses the type I interferon (IFN) response, but it is largely unknown whether and how FMDV modulates the integrated stress response. Here, we show that the stress response is suppressed during FMDV infection. Using a chimeric recombinant encephalomyocarditis virus (EMCV), in which we functionally replaced the endogenous stress response antagonist by FMDV leader protease (L) or 3C, we demonstrate an essential role for L in suppressing stress granule (SG) formation. Consistently, infection with a recombinant FMDV lacking L resulted in SG formation. Additionally, we show that L cleaves the known SG scaffold proteins G3BP1 and G3BP2 but not TIA-1. We demonstrate that the closely related equine rhinitis A virus (ERAV) L also cleaves G3BP1 and G3BP2 and also suppresses SG formation, indicating that these abilities are conserved among aphthoviruses. Neither FMDV nor ERAV L interfered with phosphorylation of RNA-dependent protein kinase (PKR) or eIF2α, indicating that L does not affect SG formation by inhibiting the PKR-triggered signaling cascade. Taken together, our data suggest that aphthoviruses actively target scaffolding proteins G3BP1 and G3BP2 and antagonize SG formation to modulate the integrated stress response. The picornavirus foot-and-mouth disease virus (FMDV) is a notorious animal pathogen that puts a major economic burden on the global livestock industry. Outbreaks have significant consequences for animal health and product safety. Like many other viruses, FMDV must manipulate antiviral host responses to establish infection. Upon infection, viral double-stranded RNA (dsRNA) is detected, which results in the activation of the RNA-dependent protein kinase (PKR)-mediated stress response, leading to a stop in cellular and viral translation and the formation of stress granules (SG), which are thought to have antiviral properties. Here, we show that FMDV can suppress SG formation via its leader protease (L). Simultaneously, we observed that L can cleave the SG scaffolding proteins G3BP1 and G3BP2. Understanding the molecular mechanisms of the antiviral host response evasion strategies of FMDV may help to develop countermeasures to control FMDV infections in the future.
与其他病毒一样，小核糖核酸病毒口蹄疫病毒（FMDV；属）是全球畜牧业中最臭名昭著的病原体之一，需要在感染中规避抗病毒的宿主反应。人们对 FMDV 如何抑制 I 型干扰素（IFN）反应有了大量的了解，但它是否以及如何调节综合应激反应在很大程度上是未知的。在这里，我们表明 FMDV 感染时会抑制应激反应。使用嵌合重组脑炎心肌炎病毒（EMCV），我们在其中通过 FMDV 前导蛋白酶（L）或 3C 功能替代内源性应激反应拮抗剂，证明了 L 在抑制应激颗粒（SG）形成中的重要作用。一致地，感染缺乏 L 的重组 FMDV 会导致 SG 形成。此外，我们表明 L 切割已知的 SG 支架蛋白 G3BP1 和 G3BP2，但不切割 TIA-1。我们证明，密切相关的马鼻炎 A 病毒（ERAV）L 也切割 G3BP1 和 G3BP2，并抑制 SG 形成，表明这些能力在口疮病毒中是保守的。FMDV 和 ERAV L 均不干扰 RNA 依赖性蛋白激酶（PKR）或 eIF2α 的磷酸化，表明 L 不会通过抑制 PKR 触发的信号级联来影响 SG 形成。总之，我们的数据表明，口疮病毒积极靶向支架蛋白 G3BP1 和 G3BP2，并拮抗 SG 形成以调节综合应激反应。小核糖核酸病毒口蹄疫病毒（FMDV）是一种臭名昭著的动物病原体，给全球畜牧业带来了巨大的经济负担。疫情对动物健康和产品安全有重大影响。像许多其他病毒一样，FMDV 必须操纵抗病毒的宿主反应来建立感染。感染后，会检测到病毒双链 RNA（dsRNA），导致 RNA 依赖性蛋白激酶（PKR）介导的应激反应激活，导致细胞和病毒翻译停止，并形成应激颗粒（SG），SG 被认为具有抗病毒特性。在这里，我们表明 FMDV 可以通过其前导蛋白酶（L）抑制 SG 形成。同时，我们观察到 L 可以切割 SG 支架蛋白 G3BP1 和 G3BP2。了解 FMDV 逃避抗病毒宿主反应的分子机制可能有助于未来开发控制 FMDV 感染的对策。
