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metabolism
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regulation of enterovirus 2A protease-associated viral IRES activities by the cell's ERK signaling cascade. The positive regulation of virus replication by the ERK cascade is mediated through effects on both the cis-cleavage of the viral polyprotein by 2Apro and its trans-cleavage of cellular eIF4GI. The ERK cascade positively regulates EV-A71-mediated cleavage of eIF4GI that establishes the cellular conditions which favour vIRES-dependent translation. This ERK-2Apro linked network coordinating vIRES efficiency is also found in other important human enteroviruses
malfunction
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a PV 2Apro variant deficient in eukaryotic initiation factor (eIF) 4GI cleavage does not increase picornavirus IRES-driven translation
malfunction
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a catalytic mutant of 2A (2Amut) fails to cleave GAB2. Deletion of GAB1 causes a decrease in phosphorylated ERK1/2, but knockdown of GAB2 has no effect on virus-mediated ERK1/2 phosphorylation
malfunction
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CVB3 mutants, that arise with passage in polyamine-depleted conditions, contain mutations in the 2A protease (EC 3.4.22.29) and 3C protease (EC 3.4.22.28). These mutant proteases confer resistance to polyamine depletion. The 2A and 3C protease mutations also enhance reporter protease activity in polyamine-depleted conditions. The mutations promote cleavage of cellular eIF4G during infection of polyamine-depleted cells
malfunction
infection of 2A protease activity-inactivated recombinant EV71 (EV71-2AC110S) failed to induce atypical stress granule (aSG) formation and only induced typical stress granule (tSG) formation, which is PKR and eIF2alpha phosphorylation-dependent. When the protease activity of 2A in EV71 is blocked (EV71-2AC110S), the tSGs but not aSGs appear in infected cells
malfunction
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overexpression of these DAP5 truncates (45 kDa N-terminal (DAP5-N) and 52 kDa C-terminal (DAP5-C) fragments) demonstrates that DAP5-N retains the capability of initiating IRES-driven translation of apoptosis-associated p53, but not the prosurvival Bcl-2 (B-cell lymphoma 2) when compared with the full-length DAP5
malfunction
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viral 2Apro proteolytic activity is key process by disrupting the ERK signaling cascade. Disruption of the ERK signaling cascade interrupts viral 2Aprocatalysed processing of eIF4GI, overview. Inhibition of the ERK signaling cascade decreases 2Apro-mediated vIRES-dependent translation in other enteroviruses
malfunction
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CVB3 mutants, that arise with passage in polyamine-depleted conditions, contain mutations in the 2A protease (EC 3.4.22.29) and 3C protease (EC 3.4.22.28). These mutant proteases confer resistance to polyamine depletion. The 2A and 3C protease mutations also enhance reporter protease activity in polyamine-depleted conditions. The mutations promote cleavage of cellular eIF4G during infection of polyamine-depleted cells
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malfunction
Enterovirus A71 BrCR
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infection of 2A protease activity-inactivated recombinant EV71 (EV71-2AC110S) failed to induce atypical stress granule (aSG) formation and only induced typical stress granule (tSG) formation, which is PKR and eIF2alpha phosphorylation-dependent. When the protease activity of 2A in EV71 is blocked (EV71-2AC110S), the tSGs but not aSGs appear in infected cells
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physiological function
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cleavage of eIF4G by PV 2Apro in mammalian cells modifies the requirement for eIF2 in translation directed by picornavirus IRESs. Cleavage of eIF4G by PV 2Apro establishes a mechanism for IRES-driven translation that is cap- and eIF2 independent
physiological function
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Poliovirus 2A protease is able to confer high translatability on picornavirus IRESs when these are transcribed from sindbis virus replicons
physiological function
2A protease is the key viral component that triggers stress granule formation
physiological function
2A protease is the key viral component that triggers stress granule formation
physiological function
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cleavage of serum response factor mediated by enteroviral protease 2A contributes to impaired cardiac function in mice
physiological function
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expression of 2A protease induces a selective nucleo-cytoplasm translocation of several important RNA binding proteins and splicing factors. The enzyme can target alternative pre-mRNA splicing by regulating protein shuttling between the nucleus and the cytoplasm. The enzyme regulates alternative splicing of the Fas exon 6
physiological function
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the enzyme binds to and stabilizes mouse double minute 4, thus in turn, it enhances the mitochondrial localization of p53 and promotes apoptosis in glioma cells
physiological function
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death-associated protein 5 (DAP5) is cleaved during CVB3 infection by coxsackievirus B3 2A protease. Viral protease 2A but not 3C (EC 3.4.22.28) is responsible for DAP5 cleavage generating 45 kDa N-terminal (DAP5-N) and 52 kDa C-terminal (DAP5-C) fragments, respectively. Cleavage of DAP5 facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes. Also eukaryotic translation initiation factor 4G (eIF4G) is cleaved during infection by the enterovirus protease leading to the shutoff of cellular cap-dependent translation, but it does not affect the initiation of cap-independent translation of mRNAs containing an internal ribosome entry site (IRES). DAP5 is cleaved at amino acid G434. Upon cleavage, DAP5-N largely translocates to the nucleus at the later time points of infection, whereas the DAP5-C largely remains in the cytoplasm. DAP5-N expression promotes CVB3 replication and progeny release. On the other hand, DAP5-C exerts a dominant-negative effect on cap-dependent translation. DAP5 is cleaved into N- and C-terminal-truncated forms during CVB3 infection in vitro and in vivo and is transcriptionally downregulated. DAP5-N and DAP5-C differentially regulate translation of p53 and Bcl-2 and result in apoptotic cell death. DAP5-N and DAP5-C differentially alter translation but not transcription of IRES-containing genes p53 and Bcl-2
physiological function
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enterovirus 2Apro plays a key role in inhibiting innate antiviral cellular responses. The direct cleavage of eIF4G by 2Apro contributes to the suppression of stress granule (SG) formation. Cleavage of eIF4G impairs the recruitment of 40S ribosomes to mRNAs, thereby altering the composition of mRNPs, which, in turn, may affect their recruitment to SGs. The observation that 2Apro triggers SG formation by cleavage of eIF4G. During enterovirus infection, several signaling molecules in the RLR pathway have been suggested to be cleaved by 2Apro and 3Cpro (EC 3.4.22.28). Enterovirus 2Apro, but not 3Cpro, suppresses the induction of IFN-alpha/beta gene transcription in HeLa cells. 2Apro is a major enteroviral security protein
physiological function
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enterovirus 2Apro plays a key role in inhibiting innate antiviral cellular responses. The direct cleavage of eIF4G by 2Apro contributes to the suppression of stress granule (SG) formation. Cleavage of eIF4G impairs the recruitment of 40S ribosomes to mRNAs, thereby altering the composition of mRNPs, which, in turn, may affect their recruitment to SGs. The observation that 2Apro triggers SG formation by cleavage of eIF4G. During enterovirus infection, several signaling molecules in the RLR pathway have been suggested to be cleaved by 2Apro and 3Cpro (EC 3.4.22.28). Enterovirus 2Apro, but not 3Cpro, suppresses the induction of IFN-alpha/beta gene transcription in HeLa cells. 2Apro is a major enteroviral security protein
physiological function
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enterovirus 2Apro plays a key role in inhibiting innate antiviral cellular responses. The direct cleavage of eIF4G by 2Apro contributes to the suppression of stress granule (SG) formation. Cleavage of eIF4G impairs the recruitment of 40S ribosomes to mRNAs, thereby altering the composition of mRNPs, which, in turn, may affect their recruitment to SGs. The observation that 2Apro triggers SG formation by cleavage of eIF4G. During enterovirus infection, several signaling molecules in the RLR pathway have been suggested to be cleaved by 2Apro and 3Cpro (EC 3.4.22.28). Enterovirus 2Apro, but not 3Cpro, suppresses the induction of IFN-alpha/beta gene transcription in HeLa cells. 2Apro is a major enteroviral security protein
physiological function
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enterovirus 2Apro plays a key role in inhibiting innate antiviral cellular responses. The direct cleavage of eIF4G by 2Apro contributes to the suppression of stress granule (SG) formation. Cleavage of eIF4G impairs the recruitment of 40S ribosomes to mRNAs, thereby altering the composition of mRNPs, which, in turn, may affect their recruitment to SGs. The observation that 2Apro triggers SG formation by cleavage of eIF4G. During enterovirus infection, several signaling molecules in the RLR pathway have been suggested to be cleaved by 2Apro and 3Cpro (EC 3.4.22.28). Enzyme 2Apro is the viral protease responsible for cleaving MAVS. Addition of recombinant 2Apro, but not 3Cpro, to cell lysates results in the appearance of MAVS cleavage products of the same size as those observed in infected cells. These cleavage products are also observed when 2Apro, but not 3Cpro, is expressed by a recombinant encephalomyocarditis virus (EMCV), a picornavirus that by itself does not cleave components of the RLR pathway. Enterovirus 2Apro, but not 3Cpro, suppresses the induction of IFN-alpha/beta gene transcription in HeLa cells. Heterologous expression of 2Apro during EMCV infection (EMCV-2Apro) nearly completely blocks IFN-beta gene transcription (about 500fold reduction) indicates that it is unlikely that suppression of SG formation by 2Apro is the major contributing factor in the viral suppression of IFN-beta gene transcription. 2Apro is a major enteroviral security protein
physiological function
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Grb2-associated binding protein 2 (GAB2) is cleaved at G238 during CV-B3 infection by viral proteinase 2A. Knockdown of GAB2 significantly inhibits the synthesis of viral protein and subsequent viral progeny production, accompanied by reduced levels of phosphorylated p38, suggesting a pro-viral function for GAB2 linked to p38 activation. Expression of the cleavage products of GAB2 does not further enhance viral replication, indicating that GAB2 cleavage results in its loss-of-function, rather than gain-of-function in supporting viral replication that represents a distinct host defense mechanism
physiological function
poliovirus 2Apro plays a leading role in autocatalytic cleavage process of poliovirus polyprotein. 2Apro is involved in cleavage of eukaryotic translation initiation factor 4G (eIF4G)
physiological function
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the 2A and 3C picornaviral proteases function to cleave both host and viral proteins. 3C protease is responsible for the majority of viral polyprotein cleavage, while 2A facilitates the cleavage between the P1 and P2 protein segments. Polyamines are crucial to protease function during picornavirus infection
physiological function
the 2A protease (2Apro) of human rhinoviruses (HRVs) plays important roles in the propagation of the virus and the modulation of host signal pathways to facilitate viral replication. The 2A protease (2Apro) specifically cleaves homologues of the human eukaryotic initiation factors eIF4GI and eIF4GII, which are required for cap-dependent mRNA translation by the ribosome. EIF4G is part of the initiation-factor complex eIF4F, which comprises the unwinding protease eIF4A and the cap-binding protein eIF4E. The complex recruits capped cellular mRNA to the ribosome for translation. Cleavage of eIF4G by HRV 2Apro impairs this process and shuts down cap-dependent translation of mRNA. Since the initiation of protein synthesis by picornaviruses is not cap-dependent, but requires the internal ribosome-entry site (IRES) present in the 5'-UTR of the picornavirus mRNA, shutting down the host cap-dependent translation machinery does not affect the synthesis of picornavirus proteins
physiological function
the 2A protease of enterovrius 71 (EV71) induces atypical stress granule (aSG), but not typical stress granule (tSG) formation, via cleavage of eIF4GI. Furthermore, 2A is required and sufficient to inhibit tSGs formation induced by EV71 infection, sodium arsenite, or heat shock. EV71-induced aSGs are beneficial to viral translation through sequestering only cellular mRNAs, but not viral mRNAs. Thus, EV71 infection induces tSG formation via the PKR-eIF2alpha pathway, and on the other hand, 2A, but not 3C protease (EC 3.4.22.28), blocks tSG formation
physiological function
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the enzymatic activity of virally encoded 2Apro is essential to the stimulation of vIRES mediated translation. Key role of ERK cascade in maintaining 2Apro proteolytic activity required to maximize EV IRES activity at different stages of viral lifecycle
physiological function
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the enzyme cleaves cellular transcription factor nuclear factor of activated T cells 5/tonicity enhancer binding protein (NFAT5/TonEBP). The 70-kDa N-terminal cleavage product (p70-NFAT5, amino acid residues 175-471 within the N-terminal fragment of NFAT5) exerts a dominant negative effect on the full-length NFAT5 protein. Elevated expression of NFAT5 to counteract viral protease cleavage, especially overexpression of a non-cleavable mutant of NFAT5, significantly inhibits CVB3 replication. Ectopic expression of NFAT5 results in elevated expression of inducible nitric oxide synthase (iNOS), a factor reported to inhibit CVB3 replication. The anti-CVB3 activity of NFAT5 is impaired during CVB3 infection due to 2A-mediated cleavage of NFAT5
physiological function
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the human rhinovirus (HRV) 3C (EC 3.4.22.28) and 2A proteases (3Cpro and 2Apro, respectively) are critical in HRV infection, as they are required for viral polyprotein processing as well as proteolysing key host factors to facilitate virus replication. 2Apro activity is required to allow 3Cpro precursor 3CD (HRV 3CD) access to the nucleus. The activity of both 2Apro and 3Cpro is required for 3CD entry into the nucleus. Temporal activities of 2Apro and 3CD/3Cpro activities in HRV serotype16 infection
physiological function
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the 2A and 3C picornaviral proteases function to cleave both host and viral proteins. 3C protease is responsible for the majority of viral polyprotein cleavage, while 2A facilitates the cleavage between the P1 and P2 protein segments. Polyamines are crucial to protease function during picornavirus infection
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physiological function
Enterovirus A71 BrCR
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the 2A protease of enterovrius 71 (EV71) induces atypical stress granule (aSG), but not typical stress granule (tSG) formation, via cleavage of eIF4GI. Furthermore, 2A is required and sufficient to inhibit tSGs formation induced by EV71 infection, sodium arsenite, or heat shock. EV71-induced aSGs are beneficial to viral translation through sequestering only cellular mRNAs, but not viral mRNAs. Thus, EV71 infection induces tSG formation via the PKR-eIF2alpha pathway, and on the other hand, 2A, but not 3C protease (EC 3.4.22.28), blocks tSG formation
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physiological function
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2A protease is the key viral component that triggers stress granule formation
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additional information
structure-function analysis of poliovirus 2A protease, three-dimensional structure homology modelling using the crystal structure of coxsakievirus B4 as a template. Protein structure and protein-ligand-drug binding site predictions. Mutation pattern, intrinsic disorder regions (IDRs), hydrophobic regions, drug binding sites (DBS) and subcellular localization are identified, overview
additional information
structure-function analysis of poliovirus 2A protease, three-dimensional structure homology modelling using the crystal structure of coxsakievirus B4 as a template. Protein structure and protein-ligand-drug binding site predictions. Mutation pattern, intrinsic disorder regions (IDRs), hydrophobic regions, drug binding sites (DBS) and subcellular localization are identified, overview
additional information
the 2A proteases of other picornaviruses such as poliovirus and coxsackievirus also induce aSG formation and blocked tSG formation
additional information
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the 2A proteases of other picornaviruses such as poliovirus and coxsackievirus also induce aSG formation and blocked tSG formation
additional information
the enzyme structure contains a conserved His-Asp-Cys catalytic triad and a Zn2+-binding site. Comparison with other 2Apro structures from enteroviruses reveals that the substrate-binding cleft of 2Apro from HRV-C15 exhibits a more open conformation, which presumably favours substrate binding, structure comparisons, overview
additional information
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the enzyme structure contains a conserved His-Asp-Cys catalytic triad and a Zn2+-binding site. Comparison with other 2Apro structures from enteroviruses reveals that the substrate-binding cleft of 2Apro from HRV-C15 exhibits a more open conformation, which presumably favours substrate binding, structure comparisons, overview
additional information
Enterovirus A71 BrCR
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the 2A proteases of other picornaviruses such as poliovirus and coxsackievirus also induce aSG formation and blocked tSG formation
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