Functional Interaction of Heterogeneous Nuclear Ribonucleoprotein C with Poliovirus RNA Synthesis Initiation Complexes

Brunner, Jo Ellen; Nguyen, Joseph H. C.; Roehl, Holger; Ho, Tri V.; Swiderek, Kristine M.; Semler, Bert L.

doi:10.1128/jvi.79.6.3254-3266.2005

Cited by 96 publications

(126 citation statements)

References 51 publications

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“…Among them, several members of the hnRNPs family have been previously shown to play a role in regulating viral replication. 7,8,39,[44][45][46][47] For examples, hnRNP C and K were documented to interact with the non-coding regions of enteroviral RNA to facilitate translation initiation and RNA synthesis. 44,45,47 Similar to our findings in the current study, enteroviral infection causes cytoplasmic redistribution and cleavage of hnRNP D and deletion of this protein results in enhanced viral replication, suggesting that hnRNA D acts as a host restriction factor against enterovirus infection.…”

Section: Discussionmentioning

confidence: 99%

“…7,8,39,[44][45][46][47] For examples, hnRNP C and K were documented to interact with the non-coding regions of enteroviral RNA to facilitate translation initiation and RNA synthesis. 44,45,47 Similar to our findings in the current study, enteroviral infection causes cytoplasmic redistribution and cleavage of hnRNP D and deletion of this protein results in enhanced viral replication, suggesting that hnRNA D acts as a host restriction factor against enterovirus infection. 7,8,39 The antiviral mechanisms of hnRNP D appear to involve negative regulation of internal ribosome entry site (IRES)-mediated translation of viral RNA via direct interaction with the IRES of enteroviruses, 7,46 and viral RNA degradation by targeting the 3′-untranslated region (UTR) of enteroviral genome.…”

Section: Discussionmentioning

confidence: 99%

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Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

et al. 2015

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We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin-protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at aminoacid 327 between glutamine and alanine, resulting in the generation of an N-and C-terminal cleavage fragment of~35 and~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection. Coxsackievirus B3 (CVB3) is a small, positive-stranded RNA enterovirus. 1 The single open reading frame of CVB3 is translated into a viral polypeptide that is subsequently cleaved by two virus-encoded proteases 2A and 3C to generate structural and non-structural proteins. 2 In addition to processing viral polyprotein, 2A and 3C target host proteins important for maintenance of protein translation and transcription, antiviral activity, and cellular architecture and signaling, contributing to virus-induced pathogenesis. [3][4][5] Although enteroviral replication takes place exclusively in the cytoplasm, viral infection has been demonstrated to lead to cytoplasmic translocation of nuclear proteins. 6 For example, heterogeneous ribonucleoprotein D (hnRNP D) has been shown to translocate from the nucleus to the cytoplasm during enteroviral infection. 5,7,8 Moreover, hnRNP D is cleaved by 3C and has an antiviral function against enteroviral infection. 5,7,8 Cytoplasmic translocation after enteroviral infection has also been demonstrated for several other hnRNPs (A1, C, and K)...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

et al. 2015

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“…Following the synthesis of viral proteins required for RNA replication, the genome also serves as the template for negative-strand-RNA synthesis. The intermediate double-stranded RNA (replicative form) is then used in the synchronous synthesis of positive-strand RNA (2,5). A large excess of positive-strand RNA transcripts is produced compared to negative-strand RNA (2).…”

mentioning

confidence: 99%

Modification of the Untranslated Regions of Human Enterovirus 71 Impairs Growth in a Cell-Specific Manner

Kok

Phuektes

Bek

et al. 2012

J Virol

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Human enterovirus 71 (HEV71) is the causative agent of hand, foot, and mouth disease and associated acute neurological disease. At present, little is known about the genetic determinants of HEV71 neurovirulence. Studies of related enteroviruses have indicated that the untranslated regions (UTRs), which control virus-directed translation and replication, also exert significant influence on neurovirulence. We used an infectious cDNA clone of a subgenogroup B3 strain to construct and characterize chimeras with 5=-and 3=-UTR modifications. Replacement of the entire HEV71 5= UTR with that of human rhinovirus 2 (HRV2) resulted in a small reduction in growth efficiency in cells of both nonneuronal (rhabdomyosarcoma) and neuronal (SH-SY5Y) origin due to reduced translational efficiency. However, the introduction of a 17-nucleotide deletion into the proximal region of the 3= UTR significantly decreased the growth of HEV71-HRV2 in SH-SY5Y cells. This observation is similar to that made with stem-loop domain Z (SLD Z)-deleted coxsackievirus B3-HRV2 5=-UTR chimeras reported previously and provides the first evidence of a potentially functional SLD Z in the 3= UTR in human enterovirus A species viruses. We further showed that the cellspecific growth impairment was caused by the synergistic effects of cis-acting UTR control elements on different stages of the virus life cycle. These chimeras will further improve our understanding of the control of HEV71 replication and its relationship to neurovirulence.

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“…This complex is required for poliovirus RNA synthesis (24,25). Protein 3CD interacts with other cellular proteins, including heterogeneous ribonucleoprotein C1/C2 (hnRNP C1/C2), which may be required for poliovirus positive-strand RNA synthesis (26,27).…”

mentioning

confidence: 99%

Viral Proteinase Requirements for the Nucleocytoplasmic Relocalization of Cellular Splicing Factor SRp20 during Picornavirus Infections

Fitzgerald

Chase

Cathcart

et al. 2013

J Virol

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Infection of mammalian cells by picornaviruses results in the nucleocytoplasmic redistribution of certain host cell proteins. These viruses interfere with import-export pathways, allowing for the cytoplasmic accumulation of nuclear proteins that are then available to function in viral processes. We recently described the cytoplasmic relocalization of cellular splicing factor SRp20 during poliovirus infection. SRp20 is an important internal ribosome entry site (IRES) trans-acting factor (ITAF) for poliovirus IRES-mediated translation; however, it is not known whether other picornaviruses utilize SRp20 as an ITAF and direct its cytoplasmic relocalization. Also, the mechanism by which poliovirus directs the accumulation of SRp20 in the cytoplasm of the infected cell is currently unknown. Work described in this report demonstrated that infection by another picornavirus (coxsackievirus B3) causes SRp20 to relocalize from the nucleus to the cytoplasm of HeLa cells, similar to poliovirus infection; however, SRp20 is relocalized to a somewhat lesser extent in the cytoplasm of HeLa cells during infection by yet another picornavirus (human rhinovirus 16). We show that expression of poliovirus 2A proteinase is sufficient to cause the nucleocytoplasmic redistribution of SRp20. Following expression of poliovirus 2A proteinase in HeLa cells, we detect cleavage of specific nuclear pore proteins known to be cleaved during poliovirus infection. We also find that expression of human rhinovirus 16 2A proteinase alone can cause efficient cytoplasmic relocalization of SRp20, despite the lower levels of SRp20 relocalization observed during rhinovirus infection compared to poliovirus. Taken together, these results further define the mechanism of SRp20 cellular redistribution during picornavirus infections, and they provide additional insight into some of the differences observed between human rhinovirus and other enterovirus infections. Members of the Picornaviridae family of viruses cause a range of diseases in humans, including poliomyelitis, myocarditis, and the common cold. Picornaviruses are small single-stranded, positive-sense RNA viruses that include the enteroviruses poliovirus and coxsackievirus, as well as human rhinoviruses (HRVs). They contain a ϳ7.0-kb-to-8.5-kb genome that consists of a single open reading frame, which is translated to generate a polyprotein that is proteolytically processed by viral proteinases into structural and nonstructural proteins. Instead of a 7-methyl guanosine cap structure, picornaviruses contain a small viral protein, VPg, covalently linked to the 5= end of the RNA. This unique protein-RNA linkage serves as a primer for viral RNA synthesis. Viral translation occurs via a cap-independent mechanism and is driven by an internal ribosome entry site (IRES) located in the long, highly structured 5= noncoding region (5= NCR).In addition to proteolytic processing of the viral polyprotein, the viral proteinases 2A and 3C/3CD cleave several cellular proteins, including eukaryotic initiation factor 4G ...

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Functional Interaction of Heterogeneous Nuclear Ribonucleoprotein C with Poliovirus RNA Synthesis Initiation Complexes

Cited by 96 publications

References 51 publications

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

Cytoplasmic translocation, aggregation, and cleavage of TDP-43 by enteroviral proteases modulate viral pathogenesis

Modification of the Untranslated Regions of Human Enterovirus 71 Impairs Growth in a Cell-Specific Manner

Viral Proteinase Requirements for the Nucleocytoplasmic Relocalization of Cellular Splicing Factor SRp20 during Picornavirus Infections

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