Cleavage of Interferon Regulatory Factor 7 by Enterovirus 71 3C Suppresses Cellular Responses

Lei, Xiaobo; Xiao, Xia; Xue, Qiang; Jin, Qi; He, Bin; Wang, Jianwei

doi:10.1128/jvi.01855-12

Cited by 142 publications

(148 citation statements)

References 35 publications

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“…Several studies have suggested that EV71 suppresses antiviral immunity (9,10,(13)(14)(15)(16)(17). In addition to inhibition of type I IFN induction, EV71 has evolved strategies to counter inflammasome activation through cleavage of NLRP3 by viral proteases 2A and 3C (18).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the 3C protease induces apoptosis by inducing cleavage of PinX1, an intrinsic telomerase inhibitor, to facilitate EV71 release (12). Other important roles of 3C are to dampen immune responses by impeding the RIG-I-MAVS interaction or by cleaving a series of host factors, including TIR domain-containing adaptor inducing IFN-␤ (TRIF), interferon regulatory factor 7/9, and TAK1/TAB1/TAB2/TAB3 complex (13)(14)(15)(16)(17).…”

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confidence: 99%

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Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Lei

Zhang

Xiao

et al. 2017

J Virol

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110

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Enterovirus 71 (EV71) can cause hand-foot-and-mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (GSDMD), an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1 to 193 (GSDMD ). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD ). This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response.IMPORTANCE Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated interleukin-1␤ (IL-1␤) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD 1-275 (p30) inhibits EV71 replication whereas GSDMD 1-193 does not. These results reveal a new strategy for EV71 to evade the antiviral response. KEYWORDS EV71, HFMD, 3C, GSDMDE nterovirus 71 (EV71) is a major etiological agent of hand-foot-and-mouth disease (HFMD) which affects infants and children younger than 5 years of age. Most of these infections are self-limited with mild symptoms, including fever and vesicular eruptions mainly on the skin of hands and feet and in the mouth. However, some patients show severe neurological diseases, including aseptic meningitis, acute flaccid paralysis, encephalitis, and pulmonary edema. Since it was first isolated in California in 1974 (1-3), EV71 infection has caused many large-scale epidemics in the world, especially in the Asia-Pacific region (1, 4-6). To date, there are no effective therapeutic drugs for EV71 infection.EV71 belongs to the Enterovirus genus of the family Picornaviridae. The viral genome is approximately 7,500 nucleotides in length, with a single open reading frame that encodes a large precursor protein that is subsequently processed into three structural (VP0, VP1, and VP3) and seven nonstructural (2A, 2B, 2C, 3A, 3B, 3C, and 3D) proteins by the virus-encoded protease 2A or 3C (7). The three structural proteins and the RNA form provirions, in which VP0 is cleaved into VP2 and VP4 by RNA or 3CD, but the

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Lei

Zhang

Xiao

et al. 2017

J Virol

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110

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“…As the result of IRF7 cleavage, EV-D68 3C pro interrupts the type I IFN response. This is reminiscent of the 3C protease encoded by EV71 that causes hand-foot-and-mouth disease and neurological complications (40). Although it does contain amino acid sequence variations, the 3C protease of EV-D68 is 53% identical to its counterpart from EV71 (56).…”

Section: Discussionmentioning

confidence: 99%

“…Plasmids pEGFPC1, pEGFP-3C and pEGFP-3C variants, pCMV6-Flag-Myc-IRF7, pGL3-IFN-␤-Luc, IFN-␣4 -Luc, and pRL-SV40 have been described elsewhere (35,40). The IRF7 mutants were constructed by using Pfu DNA polymerase (Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

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

Zou

Liu

Lei

et al. 2016

J Virol

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Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family.Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C pro , an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C pro targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C pro . Together, these results suggest that a dynamic interplay between 3C pro and IRF7 may determine the outcome of EV-D68 infection. IMPORTANCE EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C pro -IRF7 interaction may represent an interface that dictates EV-D68 infection.E nterovirus D68 (EV-D68) was first isolated from children with lower respiratory tract infections in California, USA, in 1962 and belongs to the species Enterovirus D within the Enterovirus genus, Picornaviridae (1). A global upsurge of EV-D68 infections in patients with respiratory tract infections (RTIs) has been observed in recent years (2-21). In 2014, a large outbreak of EV-D68 infections occurred in the United States, which raised public health concern owing to severe respiratory illness and neurological complications (22)(23)(24)(25)(26)(27)(28)(29)(30).Although linked to clinical disease, EV-D68 remains poorly characterized. EV-D68 is structurally similar to other enteroviruses (31). The virus possesses a genome approximately 7.4 kb in size, with the capacity to encode a large precursor that is processed into structural proteins (VP1, VP2, VP3, and VP4) and nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) (17). Viral infection initiates with sialic acids of the epithelial cells (32). In this process, the virus preferentially binds to ␣2,6-linked sialic acids rather than to ␣2,3-linked sialic acids (33). In addition, EV-D68 is able to infect leukocyte cells (34). As such, active replication of EV-D68 is thought to trigger cytokine responses (35).It is well established that the pattern-recognition receptors (PRRs) initiate innate antiviral immunity through activation of interferon regulatory factor 3 (IRF3), interferon r...

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“…The 3C viral protease of picornavirus enterovirus 71 effectively inhibits activity of both transcription factors, initially via cleavage of IRF7, rendering IRF7 functionally redundant. The cleaved N-terminus of IRF7 then binds IRF3, which inhibits nuclear translocation of IRF3 and subsequent induction of type I IFNs, and thereby facilitating viral replication (Lei, Xiao et al 2013).…”

Section: Project Aimsmentioning

confidence: 99%

The role of type I interferon in the immunobiology of chikungunya virus

Wilson¹

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause explosive outbreaks of a febrile, arthritic/arthralgic disease usually lasting weeks to months, and in rare cases, more than a year. In 2004, the largest ever CHIKV outbreak began in Kenya, spreading to islands of the Indian Ocean, India, South East Asia and major outbreaks have recently occurred in the South Pacific Islands and the Caribbean.The host type I interferon (IFN) response is crucial for effective control of CHIKV infection.Herein, the dynamics, source and responses generated by the type I IFNs following CHIKV infection were investigated. RNASeq was undertaken to examine, in detail, the nature of the type I IFN responses generated in the feet and inguinal lymph nodes of mice following CHIKV infection at days 2 and 7 post-infection. High quality sequencing data was generated from III host and viral poly-adenylated RNA, permitting investigation of low level gene transcription from both sources, and the identification of novel genes/transcripts, in addition to analysis of differential gene expression.Investigation of host transcriptional activity revealed a type I IFN dominated immune response, in spite of a low induction of type I IFN mRNA transcripts at day 2 and an absence of type I IFN mRNA induction on day 7. Many type I IFN-regulated genes, including IRF7, remained up-regulated in the feet at day 7, suggesting type I IFNindependent mechanisms for maintenance of type I IFN-regulated gene expression. Six novel IRF3 isoforms and a potentially novel protein coding gene were also identified.RNA-Seq analysis of CHIKV transcriptional activity reflected the known CHIKV replication kinetics, in which virus replicates in the joints, and spreads to the draining lymph nodes, with viral titres peaking at day 2 and largely resolving at day 7. Assessment of mutations within the CHIKV genome showed an accumulation with time, with error accumulation higher in the lymph nodes than in the feet. These studies represent the first deep sequencing analysis of CHIKV genomes in tissues.The findings in this thesis substantially add to our knowledge of the role and function of the immune response after CHIKV, illustrating for the first time that type I IFNs protect against haemorrhagic shock and that expression of type I IFN inducible genes is maintained well after type I IFN induction has waned.

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Cleavage of Interferon Regulatory Factor 7 by Enterovirus 71 3C Suppresses Cellular Responses

Cited by 142 publications

References 35 publications

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

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

The role of type I interferon in the immunobiology of chikungunya virus

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