3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

Zou, Xiang; Liu, Lulu; Lei, Xiaobo; Zhou, Zhuo; He, Bin; Wang, Jianwei

doi:10.1128/jvi.02395-15

Cited by 61 publications

(61 citation statements)

References 57 publications

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“…6D) expression was also not affected by CV-A16 3C pro . It was reported previously that the EV-A71 and EV-D68 3C pro proteins induce the cleavage of IRF7 (37,39). We did not detect a cleaved IRF7 product in the presence of CV-A16 3C pro (Fig.…”

Section: Resultssupporting

confidence: 54%

“…Increasing evidence suggests that EV-A71 3C pro targets innate immune factors, such as RIG-I, TRIF, IRF7/9, the TAK1/TAB1/TAB2/TAB3 complex, and NLRP3, to modulate type I IFN and cytokine responses (34)(35)(36)(37)(38). Recently, EV-D68 3C pro has been reported to target IRF7 and TRIF to disable innate sensing responses (39,40). However, little is known about the function of the CV-A16 and CV-A6 3C pro proteins in innate immunity.…”

mentioning

confidence: 99%

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Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

Rui

Wang

et al. 2017

J Virol

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Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picornaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3C pro proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3C pro proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3C pro proteins all cleave transforming growth factor ␤-activated kinase 1 (TAK1), resulting in the inhibition of NF-B activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3C pro proteins from diverse enteroviruses and coxsackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy.IMPORTANCE CV-A16, CV-A6, and EV-D68 are emerging pathogens associated with hand, foot, and mouth disease and pediatric respiratory disease worldwide. The pathogenic mechanisms of these viruses are largely unknown. Here we demonstrate that the CV-A16, CV-A6, and EV-D68 3C pro proteins block MDA5-triggered type I IFN induction. The 3C pro proteins of these viruses bind MDA5 and inhibit its interaction with MAVS. In addition, the CV-A16, CV-A6, and EV-D68 3C pro proteins cleave TAK1 to inhibit the NF-B response. Thus, our data demonstrate that circulating HFMDassociated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed a mechanism to subvert host innate immune responses by simultaneously targeting key factors in the RLR and TLR pathways. These findings indicate the potential merit of targeting the CV-A16, CV-A6, and EV-D68 3C pro proteins as an antiviral strategy.KEYWORDS MDA5, TAK1, MAVS, 3C protease, CV-A16, CV-A6, EV-D68, HFMD, innate immune response

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Section: Resultssupporting

confidence: 54%

mentioning

confidence: 99%

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

Rui

Wang

et al. 2017

J Virol

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“…During enterovirus infection, several signaling molecules in the RLR pathway have been suggested to be cleaved by 2A pro (MDA5 and MAVS) and 3C pro (RIG-I, MAVS, IRF7, and IRF9) (21,23,26,27,29,44,45). There are conflicting observations, and the question remained of which, if any, of the identified cleavages is important for inhibiting IFN-␣/␤ gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Both viral proteases, 2A pro and 3C pro , cleave various factors of the RLR signaling pathway, implicating them in the suppression of IFN-␣/␤ gene transcription. Overexpression of 3C pro of several enteroviruses has been shown to result in the cleavage of MAVS, IRF7, and IRF9 and, as a consequence, in the suppression of a coexpressed IFN reporter construct (24)(25)(26)(27)(28). However, in several of these studies, convincing evidence that the cleavage products observed upon 3C pro overexpression are the same as those observed in enterovirus-infected cells is lacking.…”

mentioning

confidence: 99%

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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“…IRF7 stimulates type‐I IFN production, such as IFNα, thereby activating the JAK‐STAT pathway in adjacent cells . The 3C pro of EV‐A71 can process IRF7 at a cleavage site between Gln189 and Ser190 in vitro and in vivo , while the 3C pro of EV‐D68 does so at two sites (Gln167↓Ala168 and Gln180↓S190) .…”

Section: Rna‐virus Proteases Interfering With the Host Innate Immune mentioning

confidence: 99%

RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

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3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

Cited by 61 publications

References 57 publications

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

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

RNA‐virus proteases counteracting host innate immunity

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