Enterovirus 71 inhibits cytoplasmic stress granule formation during the late stage of infection

Zhang, Yating; Yao, Lili; Xu, Xin; Han, Huansheng; Li, Pengfei; Zou, Dehua; Li, Xingzhi; Zheng, Liang; Cheng, Lixin; Shen, Yujiang; Wang, Xianhe; Wu, Xilin; Xu, Jiaxin; Song, Baifen; Xu, Shuyan; Zhang, Hua; Cao, Hongwei

doi:10.1016/j.virusres.2018.07.006

Cited by 17 publications

(23 citation statements)

References 33 publications

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“…1). Suppression of SG formation was previously reported for PV (34), for CV-B3 (35), and-while this work was in progress-also for EV-A71 (36,37). Here, we provide evidence that CV-A21, another member of the EV-C species, and EV-D68, an EV-D species member, also suppress the formation of SGs.…”

Section: Resultssupporting

confidence: 85%

“…Enteroviruses also actively suppress the ISR. Infection of cells with PV, CV-B3, and EV-A71 results in the formation of small SGs early in infection, but these disappear later in infection (34)(35)(36)(37). Again, conflicting observations about the identity of the viral antagonist have been reported.…”

mentioning

confidence: 99%

“…Again, conflicting observations about the identity of the viral antagonist have been reported. Initially, the suppression of SGs was attributed to 3C pro (34)(35)(36). 3C pro was shown to cleave G3BP1 and suppress SG formation, and overexpression of a cleavage-resistant G3BP1 decreased virus replication, although this decrease was rather modest (34,36,38).…”

mentioning

confidence: 99%

“…Initially, the suppression of SGs was attributed to 3C pro (34)(35)(36). 3C pro was shown to cleave G3BP1 and suppress SG formation, and overexpression of a cleavage-resistant G3BP1 decreased virus replication, although this decrease was rather modest (34,36,38). Recently, however, evidence was presented that 2A pro from EV-A71, PV, or CV suppresses SG formation induced by infection, as well as that induced by sodium arsenite or heat shock (37).…”

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confidence: 99%

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Essential Role of Enterovirus 2A Protease in Counteracting Stress Granule Formation and the Induction of Type I Interferon

Visser

Langereis

Rabouw

et al. 2019

J Virol

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Most viruses have acquired mechanisms to suppress antiviral alpha/beta interferon (IFN-␣/␤) and stress responses. Enteroviruses (EVs) actively counteract the induction of IFN-␣/␤ gene transcription and stress granule (SG) formation, which are increasingly implicated as a platform for antiviral signaling, but the underlying mechanisms remain poorly understood. Both viral proteases (2A pro and 3C pro ) have been implicated in the suppression of these responses, but these conclusions predominantly rely on ectopic overexpression of viral proteases or addition of purified viral proteases to cell lysates. Here, we present a detailed and comprehensive comparison of the effect of individual enterovirus proteases on the formation of SGs and the induction of IFN-␣/␤ gene expression in infected cells for representative members of the enterovirus species EV-A to EV-D. First, we show that SG formation and IFN-␤ induction are suppressed in cells infected with EV-A71, coxsackie B3 virus (CV-B3), CV-A21, and EV-D68. By introducing genes encoding CV-B3 proteases in a recombinant encephalomyocarditis virus (EMCV) that was designed to efficiently activate antiviral responses, we show that CV-B3 2A pro , but not 3C pro , is the major antagonist that counters SG formation and IFN-␤ gene transcription and that 2A pro 's proteolytic activity is essential for both functions. 2A pro efficiently suppressed SG formation despite protein kinase R (PKR) activation and ␣ subunit of eukaryotic translation initiation factor 2 phosphorylation, suggesting that 2A pro antagonizes SG assembly or promotes its disassembly. Finally, we show that the ability to suppress SG formation and IFN-␤ gene transcription is conserved in the 2A pro of EV-A71, CV-A21, and EV-D68. Collectively, our results indicate that enterovirus 2A pro plays a key role in inhibiting innate antiviral cellular responses. IMPORTANCE Enteroviruses are important pathogens that can cause a variety of diseases in humans, including aseptic meningitis, myocarditis, hand-foot-and-mouth disease, conjunctivitis, and acute flaccid paralysis. Like many other viruses, enteroviruses must counteract antiviral cellular responses to establish an infection. It has been suggested that enterovirus proteases cleave cellular factors to perturb antiviral pathways, but the exact contribution of viral proteases 2A pro and 3C pro remains elusive. Here, we show that 2A pro , but not 3C pro , of all four human EV species (EV-A to EV-D) inhibits SG formation and IFN-␤ gene transcription. Our observations suggest that enterovirus 2A pro has a conserved function in counteracting antiviral host responses and thereby is the main enterovirus "security protein." Understanding the molecular mechanisms of enterovirus immune evasion strategies may help to develop countermeasures to control infections with these viruses. FIG 5 Enterovirus 2A pro suppresses the induction of type I IFN gene expression. (A)HeLa R19 cells were infected with the indicated viruses at an MOI of 10, and the cells were lysed at 8 hpi, total cell...

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Section: Resultssupporting

confidence: 85%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Essential Role of Enterovirus 2A Protease in Counteracting Stress Granule Formation and the Induction of Type I Interferon

Visser

Langereis

Rabouw

et al. 2019

J Virol

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“…Plasmid pEGFP-LC3, indicator of autophagy, was kindly provided by prof. Xiaojun Wang (Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences). PEDV genome was extracted from virus stock with TRIzol reagent, and was used as template to amplify the PEDV orf3 gene fragment using RT-PCR method according to our experimental methods (Zhang et al, 2018). Plasmid of the PEDV ORF3 fused with GFP tag was designed by cloning the open reading frame (ORF) of orf3 into the Xho I and Bam HI sites of the pEGFP-N1 vector.…”

Section: Plasmids and Transfectionmentioning

confidence: 99%

Porcine epidemic diarrhea virus ORF3 protein causes endoplasmic reticulum stress to facilitate autophagy

Zou

Duan

et al. 2019

Veterinary Microbiology

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A B S T R A C TPorcine epidemic diarrhea virus (PEDV), the causative agent of PED, is an enveloped, positive-stranded RNA virus in the genus Alphacoronavirus, family Coronaviridae, order Nidovirales. PEDV non-structural accessory protein ORF3 is an ion channel related to viral infectivity and pathogenicity. Our previous study showed that PEDV ORF3 has expression characteristic of aggregation in cytoplasm, but its biological function remains elusive. Thus in this study, we initiated the construction of various vectors to express ORF3, and found ORF3 localized in the cytoplasm in the aggregation manner. Subsequently, confocal microscopy analysis showed that the aggregated ORF3 localized in endoplasmic reticulum (ER) to trigger ER stress response via up-regulation of GRP78 protein expression and activation of PERK-eIF2α signaling pathway. In addition, our results showed that PEDV ORF3 could induce the autophagy through inducing conversion of LC3-I to LC3-II, but couldn't influence the apoptosis. In contrast, conversion of LC3-I/LC3-II could be significantly inhibited by 4-PBA, an ER stress inhibitor, indicating that ORF3-induced autophagy is dependent on ER stress response. This work not only provides some new findings for the biological function of the PEDV ORF3 protein, but also help us for the further understanding the molecular interaction between PEDV ORF3 protein and cells.

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A little less aggregation a little more replication: Viral manipulation of stress granules

Brownsword

Locker

2022

WIREs RNA

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Recent exciting studies have uncovered how membrane‐less organelles, also known as biocondensates, are providing cells with rapid response pathways, allowing them to re‐organize their cellular contents and adapt to stressful conditions. Their assembly is driven by the phase separation of their RNAs and intrinsically disordered protein components into condensed foci. Among these, stress granules (SGs) are dynamic cytoplasmic biocondensates that form in response to many stresses, including activation of the integrated stress response or viral infections. SGs sit at the crossroads between antiviral signaling and translation because they concentrate signaling proteins and components of the innate immune response, in addition to translation machinery and stalled mRNAs. Consequently, they have been proposed to contribute to antiviral activities, and therefore are targeted by viral countermeasures. Equally, SGs components can be commandeered by viruses for their own efficient replication. Phase separation processes are an important component of the viral life cycle, for example, driving the assembly of replication factories or inclusion bodies. Therefore, in this review, we will outline the recent understanding of this complex interplay and tug of war between viruses, SGs, and their components. This article is categorized under: RNA in Disease and Development > RNA in Disease Translation > Regulation RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes

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Enterovirus 71 inhibits cytoplasmic stress granule formation during the late stage of infection

Cited by 17 publications

References 33 publications

Essential Role of Enterovirus 2A Protease in Counteracting Stress Granule Formation and the Induction of Type I Interferon

Essential Role of Enterovirus 2A Protease in Counteracting Stress Granule Formation and the Induction of Type I Interferon

Porcine epidemic diarrhea virus ORF3 protein causes endoplasmic reticulum stress to facilitate autophagy

A little less aggregation a little more replication: Viral manipulation of stress granules

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