Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein

Li, Jing; Yao, Yunfang; Xu, Xiao; Lin, Yan; Yang, Zhilong; Qiao, Wentao; Tan, Juan

doi:10.1128/jvi.02016-16

Cited by 39 publications

(35 citation statements)

References 41 publications

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“…We along with others have reported that 3C can mediate cleavage of host factors and affect their functions (12,35,36). To investigate whether EV71 3C targets GSDMD, we conducted cleavage experiments.…”

Section: Resultsmentioning

confidence: 99%

“…3C induces apoptosis through caspase activation (11) to facilitate viral spread or pathogenesis. 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

114

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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: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Lei

Zhang

Xiao

et al. 2017

J Virol

114

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“…3C pro can induce apoptosis (12)(13)(14), cleave certain cellular factors required for transcription, translation and activation of innate immunity (5,(15)(16)(17) (18). As strong antagonists of IFNs, EVD68 and EV71 3C pro downregulate or directly cleave interferon regulatory factor 7 (IRF7), the downstream molecule of TLRs and TLR signaling pathway, and inhibit innate antiviral immunity (5,19).…”

Section: Introductionmentioning

confidence: 99%

Picornavirus 3C proteins inhibit RIG-I-mediated innate immune responses by reducing TRIM25 expression

Xiao

et al. 2020

Preprint

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Background：Enterovirus (EV) 3C proteins suppress type I interferon (IFN) responses mediated by retinoid acid-inducible gene I (RIG-I). An E3 ubiquitin ligase, tripartite motif protein 25 (TRIM25)-mediated RIG-I ubiquitination is essential for RIG-I antiviral activity. However, whether the effect of EV 3C on RIG-I is associated with TRIM25 remains unknown.Methods：In this study，luciferase reporter assays was used to detected the activity of IFN-β. Western Blot was used to detected the expression of proteins. Real-time PCR are used to detect that the mRNAs expression. And the co-immunoprecipitation assay was used to detect the interaction between TRIM25 and 3C protein.Results：Here, we demonstrated that 3C proteins of EV71 and CVB3 reduced the expression of RIG-I and TRIM25 through protease cleavage activities. Overexpression of TRIM25 restored RIG-I expression and IFN production reduced by 3C proteins. Further investigation confirmed that the two amino acids in TRIM25 required for RIG-I ubiquitination and structural conformation of TRIM25 were essential for RIG-I recovery. Moreover, we observed that TRIM25 could rescue RIG-I expression reduced by CVA6and EVD68 but not CVA16 3C.Conclusions：Our findings provide an insightful interpretation of 3C protein-mediated host innate immune suppression and support TRIM25 as an attractive target against EV infection.

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“…They found that the proteolytic activity of 3C pro triggers apoptosis in the SF268 cells through a mechanism involving caspase activation, and that this apoptotic pathway might play an important role in the pathogenesis of EV-A71 infection (Li et al, 2002 ). 3C pro also promoted apoptosis by cleaving PinX1 (a telomere-binding protein) using its protease activity, and that this cleavage facilitated EV-A71 release (Li J. et al, 2017 ). Further, it was reported that SUMOylation (where SUMO is small ubiquitin-like modifier) promotes EV-A71 3C pro ubiquitination, leading to degradation, correlating with a decrease in viral replication and cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Enterovirus A71 Proteins: Structure and Function

Yuan

Шен

et al. 2018

Front. Microbiol.

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Enterovirus A71 (EV-A71) infection has grown to become a serious threat to global public health. It is one of the major causes of hand, foot, and mouth disease (HFMD) in infants and young children. EV-A71 can also infect the central nervous system (CNS) and induce diverse neurological complications, such as brainstem encephalitis, aseptic meningitis, and acute flaccid paralysis, or even death. Viral proteins play a crucial role in EV-A71 infection. Many recent studies have discussed the structure and function of EV-A71 proteins, and the findings reported will definitely aid the development of vaccines and therapeutic approaches. This article reviews the progress in the research on the structure and function of EV-A71 proteins. Available literature can provide a basis for studying the pathogenesis of EV-A71 infection in detail.

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Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein

Cited by 39 publications

References 41 publications

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

Picornavirus 3C proteins inhibit RIG-I-mediated innate immune responses by reducing TRIM25 expression

Enterovirus A71 Proteins: Structure and Function

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