RNA interference against Enterovirus 71 infection

Sim, Adrian Chong Nyi; Luhur, Arthur; Tan, Thiam Soon; Chow, Vincent T. K.; Poh, Chit Laa

doi:10.1016/j.virol.2005.06.047

Cited by 58 publications

(39 citation statements)

References 21 publications

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“…The 3C protein of EV71 is an essential factor in viral replication (2,3). Besides viral protein processing, the 3C protein acts to inhibit antiviral immunity (6,7).…”

Section: Discussionmentioning

confidence: 99%

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

Lei

Xiao

Xue

et al. 2013

J Virol

144

153

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bEnterovirus 71 (EV71) is a positive-stranded RNA virus which is capable of inhibiting innate immunity. Among virus-encoded proteins, the 3C protein compromises the type I interferon (IFN-I) response mediated by retinoid acid-inducible gene-I (RIG-I) or Toll-like receptor 3 that activates interferon regulatory 3 (IRF3) and IRF7. In the present study, we report that enterovirus 71 downregulates IRF7 through the 3C protein, which inhibits the function of IRF7. When expressed in mammalian cells, the 3C protein mediates cleavage of IRF7 rather than that of IRF3. This process is insensitive to inhibitors of caspase, proteasome, lysosome, and autophagy. H40D substitution in the 3C active site abolishes its activity, whereas R84Q or V154S substitution in the RNA binding motif has no effect. Furthermore, 3C-mediated cleavage occurs at the Q189-S190 junction within the constitutive activation domain of IRF7, resulting in two cleaved IRF7 fragments that are incapable of activating IFN expression. Ectopic expression of wild-type IRF7 limits EV71 replication. On the other hand, expression of the amino-terminal domain of IRF7 enhances EV71 infection, which correlates with its ability to interact with and inhibit IRF3. These results suggest that control of IRF7 by the 3C protein may represent a viral mechanism to escape cellular responses.

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“…The 3C protein of EV71 is an essential factor in viral replication (2,3). Besides viral protein processing, the 3C protein acts to inhibit antiviral immunity (6,7).…”

Section: Discussionmentioning

confidence: 99%

“…This precursor is processed into structural (VP1, VP2, VP3, and VP4) and nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) during virus infection (1). The 3C protein expressed by EV71 is essential for viral replication (2,3). In addition to its activity in viral protein processing (4), the 3C protein is linked to a number of biological processes.…”

mentioning

confidence: 99%

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

Lei

Xiao

Xue

et al. 2013

J Virol

144

153

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“…3D, F, and H). Neither the lysosome inhibitor NH 4 Cl nor the proteasome inhibitor MG132 blocked the cleavage of TAK1 components by 3C (data not shown).…”

Section: Resultsmentioning

confidence: 91%

“…This precursor is proteolytically cleaved to four structural and seven nonstructural proteins during virus infection (1). The nonstructural protein 3C is essential for the precursor cleavage and viral replication (2)(3)(4). It also possesses RNA-binding activity (3).…”

mentioning

confidence: 99%

Enterovirus 71 3C Inhibits Cytokine Expression through Cleavage of the TAK1/TAB1/TAB2/TAB3 Complex

Lei

Han

Xiao

et al. 2014

J Virol

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Enterovirus 71 (EV71) causes hand, foot, and mouth disease in young children and infants. Severe infection with EV71 can lead to various neurological complications or fatal diseases. However, the mechanism of EV71 pathogenesis is poorly understood. Emerging evidence suggests that EV71 modulates type I interferon (IFN) and cytokine responses. Here, we show that EV71 disables components of the TAB2 complex through the 3C protein. When expressed in mammalian cells, EV71 3C interacts with TAB2 and TAK1, which inhibits NF-B activation. Furthermore, 3C mediates cleavage of TAB2 and its partners, which requires the protease activity. H40D or C147S substitution in the 3C active sites abolishes its activity, whereas R84Q or V154S substitution in the RNA binding domain has no effect. The 3C protein targets TAB2 at Q113-S114, TAK1 at Q360-S361, TAB1 both at Q414-G415 and Q451-S452, and TAB3 at Q173-G174 and Q343-G344. Importantly, overexpression of TAB2 inhibits EV71 replication, whereas addition of cleaved fragments has no effect. Thus, an equilibrium between the TAB2 complex and EV71 3C represents a control point of viral infection. These results suggest that TAK1/TAB1/TAB2/TAB3 cleavage mediated by EV71 may be a mechanism to interfere with inflammatory responses. IMPORTANCEThe TAK1 complex plays a critical role in the activation of NF-B and cytokine production. However, little is known about its connection to enterovirus 71 (EV71). We demonstrate that EV71 3C suppresses cytokine expression via cleavage of the TAK1 complex proteins. EV71 3C interacts with TAB2 and TAK1. Furthermore, overexpression of TAB2 inhibits EV71 replication, whereas addition of cleaved fragment has no effect. These results suggest that the interplay of EV71 and the TAK1 complex influences the outcome of viral infection. E nterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD) in young children and infants. Severe infection with EV71 can lead to various neurological complications or even fatal diseases (1). To date, there is no effective treatment for EV71 infection. EV71 is a member of the Picornaviridae family with a single, positive-stranded RNA genome which encodes a single polyprotein precursor. This precursor is proteolytically cleaved to four structural and seven nonstructural proteins during virus infection (1). The nonstructural protein 3C is essential for the precursor cleavage and viral replication (2-4). It also possesses RNA-binding activity (3). Recent reports show that EV71 3C inhibits type I interferon (IFN) responses by targeting innate immune factors, such as RIG-I, TRIF, interferon regulatory factor 7 (IRF7), and IRF9 (5-8).Transforming growth factor-␤-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, which is activated by various stimuli, including Toll-like receptor (TLR) ligands, tumor necrosis factor alpha (TNF-␣), and interleukin-1␤ (IL-1␤) (9, 10). In mammalian cells, TAK1 constitutively binds to the TAK1 binding protein 1 (TAB1), w...

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“…Enterovirus infections, such as poliovirus (Gitlin et al, 2002), enterovirus 70 and 71 (Lu et al, 2004;Sim et al, 2005;Tan et al, 2007aTan et al, , b, 2008, coxsackievirus A16 (CAV16) (Wu et al, 2008) and CBV3 (Merl et al, 2005;Merl & Wessely, 2007;Schubert et al, 2005;Werk et al, 2005;Yuan et al, 2005) infections have been successfully inhibited using RNAi in cell culture and in animal models (Fechner et al, 2008;Kim et al, 2008;Merl et al, 2005;Tan et al, 2007b). These studies have employed sequencespecific siRNAs or hairpin RNAs, synthesized chemically or transcribed by DNA-dependent RNA polymerases.…”

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confidence: 99%

Inhibition of coxsackievirus B3 and related enteroviruses by antiviral short interfering RNA pools produced using φ6 RNA-dependent RNA polymerase

Nygårdas

Vuorinen

Aalto

et al. 2009

Journal of General Virology

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Coxsackievirus B3 (CBV3) is a member of the human enterovirus B species and a common human pathogen. Even though much is known about the enteroviral life cycle, no specific drugs are available to treat enterovirus infections. RNA interference (RNAi) has evolved to be an important tool for antiviral experimental therapies and gene function studies. We describe here a novel approach for RNAi against CBVs by using a short interfering (siRNA) pool covering 3.5 kb of CBV3 genomic sequence. The RNA-dependent RNA polymerase (RdRP) of bacteriophage w6 was used to synthesize long double-stranded RNA (dsRNA) from a cloned region (nt 3837-7399) of the CBV3 genome. The dsRNA was cleaved using Dicer, purified and introduced to cells by transfection. The siRNA pool synthesized using the w6 RdRP (w6-siRNAs) was considerably more effective than single-site siRNAs. The w6-siRNA pool also inhibited replication of other enterovirus B species, such as coxsackievirus B4 and coxsackievirus A9.

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RNA interference against Enterovirus 71 infection

Cited by 58 publications

References 21 publications

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

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

Enterovirus 71 3C Inhibits Cytokine Expression through Cleavage of the TAK1/TAB1/TAB2/TAB3 Complex

Inhibition of coxsackievirus B3 and related enteroviruses by antiviral short interfering RNA pools produced using φ6 RNA-dependent RNA polymerase

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