Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-κB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-κB Signaling through Cleavage of TANK

Huang, Lan; Liu, Qinfang; Zhang, Lijie; Zhang, Quan; Hu, Liang; Li, Changyao; Wang, Shengnan; Li, Jiangnan; Zhang, Yuanfeng; Yu, Huibin; Wang, Yan; Zhong, Zhaohua; Xiong, Tingting; Xia, Xueshan; Wang, Xiaojun; Yu, Li; Deng, Guohua; Cai, Xuehui; Cui, Shangjin; Weng, Changjiang

doi:10.1074/jbc.m115.660761

Cited by 49 publications

(53 citation statements)

References 55 publications

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“…7K and L). Similar to the case with a previous study (40), we found that the C-terminal (residues 272 to 425) fragment of TANK could not be detected in transfected cells. Thus, we did not assess its effect on IFN-␤ production.…”

Section: Resultssupporting

confidence: 91%

“…8D and F). These results are consistent with previous findings (40,41,52). These findings, to a certain extent, probably can answer why different degrees of inflammation were observed in SVV-infected animals.…”

Section: Discussionsupporting

confidence: 93%

“…6D). Similar to the case with a previously reported study (40), we found that the N-terminal (residues 292 to 425) cleavage fragment of TANK is unstable in cells. Moreover, our data demonstrated that the fragments of MAVS, TRIF, and TANK cleaved by SVV 3C pro lost the ability to induce the production of IFN-␤ (Fig.…”

Section: Discussionsupporting

confidence: 92%

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Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Qian

Fan

Liu

et al. 2017

J Virol

107

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Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-␤ (TRIF), and TRAF family member-associated NF-B activator (TANK), via viral 3C protease (3C pro ). SVV 3C pro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-B activation. SVV was also found to be sensitive to IFN-␤. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules. IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3C pro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for the Toll-like receptor 3 (TLR3)-mediated and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated signaling pathway. We also found that SVV is sensitive to IFN-␤. These findings increase our understanding of the interaction between SVV and host innate immunity.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 93%

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Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Qian

Fan

Liu

et al. 2017

J Virol

107

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“…In addition to its role in viral polyprotein processing, 3C pro proteins of certain enteroviruses have been shown to play a pivotal role in suppressing IFN-␤ production (35)(36)(37)(38)(47)(48)(49)(50)(51). However, the role of the 3C pro proteins of CV-A16, CV-A6, and EV-D68 in suppressing IFN-␤ activation has not been well characterized.…”

Section: Resultsmentioning

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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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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“…Western blotting analysis was performed as previously described (Huang et al, 2015). For confocal microscopy, BHK-21 cells were infected with EMCV-HB10, rEMCV-C 9 , rC 9 -MCS-D2A or rC 9 -EGFP-D2A at an MOI of 0.1.…”

Section: Methodsmentioning

confidence: 99%

An attenuated EMCV-HB10 strain acts as a live viral vector delivering a foreign gene

Huang

Zhang

et al. 2016

Journal of General Virology

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We successfully constructed a full-length cDNA infectious clone of the encephalomyocarditis virus (EMCV) HB10 strain and obtained a partially attenuated rEMCV-C 9 virus with a shorter poly(C) tract. Our results showed that the length of the EMCV-HB10 poly(C) tract was related to the pathogenicity of the EMCV-HB10 strain in vivo. Using pEMCV-C 9 as the backbone, we constructed the novel viral vector pC 9 -MCS-D2A by inserting a cDNA fragment containing a 127 amino acid deletion in the 2A protein, a primary cleavage cassette, a FLAG tag and a multiple cloning site (MCS) at the junction of VP1 and D2A. Additionally, the enhanced green fluorescent protein (egfp) gene was cloned into the MCS of pC 9 -MCS-D2A to test its capacity to express foreign proteins. Insertion of the egfp gene did not affect viral replication, and a decrease in EGFP expression was observed within five serial passages. Furthermore, we found that rC 9 -EGFP-D2A was avirulent in vivo, induced neutralizing antibody production and conferred protective immune responses against lethal challenge with EMCV in mice. Taken together, our results demonstrated that we had constructed an attenuated live vector based on an EMCV-HB10 strain with two modified critical virulence factors (the poly(C) tract and 2A protein) that could be used as a candidate live vaccine and a potential live viral vector for foreign antigen delivery.

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Encephalomyocarditis Virus 3C Protease Relieves TRAF Family Member-associated NF-κB Activator (TANK) Inhibitory Effect on TRAF6-mediated NF-κB Signaling through Cleavage of TANK

Cited by 49 publications

References 55 publications

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage

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

An attenuated EMCV-HB10 strain acts as a live viral vector delivering a foreign gene

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