Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways

Ullmer, Wendy; Semler, Bert L.

doi:10.3390/v8120335

Cited by 21 publications

(21 citation statements)

References 156 publications

(205 reference statements)

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“…Both termini of viral RNA genomes (and their complementary sequences) are known to be vulnerable targets for the host cell 5=-and 3=-exonucleases (200). Genome truncation is usually accompanied by a more or less marked loss of fitness and is a subject of numerous studies (see below).…”

Section: Genome Truncation and Disruptionmentioning

confidence: 99%

“…On the other hand, situations involving disruptions of viral genomes are very rarely investigated directly due to significant experimental difficulties. Yet losses of genome integrity are expected to occur often enough due to several mechanisms, such as activities of defensive antiviral nucleases (e.g., RNase L) and endoribonucleases involved in RNA interference as well as various mechanisms of host mRNA decay, including the nonsense-mediated one (200)(201)(202). The involvement of the latter is expected due to the likely presence of stop codons in the viral quasispecies caused by the infidelity of replication.…”

Section: Genome Truncation and Disruptionmentioning

confidence: 99%

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Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

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Section: Genome Truncation and Disruptionmentioning

confidence: 99%

Section: Genome Truncation and Disruptionmentioning

confidence: 99%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

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“…Venezulean equine encephalitis virus and Sindbis virus) possess high-affinity binding sites for HuR protein, a well-characterized cellular RNA stabilizer that protects transcripts from premature deadenylation and decay (9 -12). Polioviruses target several RNA decay factors for proteolytic cleavage, sponge several RNA-binding proteins, and possess an RNA element that inhibits endoribonuclease RNase L (13). Flaviviruses (e.g.…”

mentioning

confidence: 99%

Identification of phlebovirus and arenavirus RNA sequences that stall and repress the exoribonuclease XRN1

Charley

Wilusz

2018

Journal of Biological Chemistry

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Regulated mRNA decay plays a vital role in determining both the level and quality of cellular gene expression. Viral RNAs must successfully evade this host RNA decay machinery to establish a productive infection. One way for RNA viruses to accomplish this is to target the cellular exoribonuclease XRN1, because this enzyme is accessible in the cytoplasm and plays a major role in mRNA decay. Members of the Flaviviridae use RNA structures in their 5'- or 3'-untranslated regions to stall and repress XRN1, effectively stabilizing viral RNAs while also causing significant dysregulation of host cell mRNA stability. Here, we use a series of biochemical assays to demonstrate that the 3'-terminal portion of the nucleocapsid (N) mRNA of Rift Valley fever virus, a phlebovirus of the Bunyaviridae family, also can effectively stall and repress XRN1. The region responsible for impeding XRN1 includes a G-rich portion that likely forms a G-quadruplex structure. The 3'-terminal portions of ambisense-derived transcripts of multiple arenaviruses also stalled XRN1. Therefore, we conclude that RNAs from two additional families of mammalian RNA viruses stall and repress XRN1. This observation. emphasizes the importance and commonality of this viral strategy to interfere with the 5'-to-3'-exoribonuclease component of the cytoplasmic RNA decay machinery.

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“…The proposed model predicts that the binding of the complex at the 5′ end of nascent positive sense strands acts to reinitiate the synthesis of subsequent copies of positive-sense RNA on the same negative-strand template [29]. Additionally, the PCBP2/3CD pro RNP complex also has been shown to stabilize the viral RNA [30][31][32], given that picornavirus RNA is uncapped and, as such, is subject to degradation by host exonucleases [33]. Binding of PCBP2 and 3CD pro to the poliovirus 5′ cloverleaf structure.…”

Section: Introductionmentioning

confidence: 99%

Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation

Holmes

Zagnoli-Vieira

Caldecott

et al. 2020

Viruses

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In this study, we characterized the role of host cell protein tyrosyl-DNA phosphodiesterase 2 (TDP2) activity, also known as VPg unlinkase, in picornavirus infections in a human cell model of infection. TDP2/VPg unlinkase is used by picornaviruses to remove the small polypeptide, VPg (Virus Protein genome-linked, the primer for viral RNA synthesis), from virus genomic RNA. We utilized a CRISPR/Cas-9-generated TDP2 knock out (KO) human retinal pigment epithelial-1 (hRPE-1) cell line, in addition to the wild type (WT) counterpart for our studies. We determined that in the absence of TDP2, virus growth kinetics for two enteroviruses (poliovirus and coxsackievirus B3) were delayed by about 2 h. Virus titers were reduced by ~2 log10 units for poliovirus and 0.5 log10 units for coxsackievirus at 4 hours post-infection (hpi), and by ~1 log10 unit at 6 hpi for poliovirus. However, virus titers were nearly indistinguishable from those of control cells by the end of the infectious cycle. We determined that this was not the result of an alternative source of VPg unlinkase activity being activated in the absence of TPD2 at late times of infection. Viral protein production in TDP2 KO cells was also substantially reduced at 4 hpi for poliovirus infection, consistent with the observed growth kinetics delay, but reached normal levels by 6 hpi. Interestingly, this result differs somewhat from what has been reported previously for the TDP2 KO mouse cell model, suggesting that either cell type or species-specific differences might be playing a role in the observed phenotype. We also determined that catalytically inactive TDP2 does not rescue the growth defect, confirming that TDP2 5′ phosphodiesterase activity is required for efficient virus replication. Importantly, we show for the first time that polysomes can assemble efficiently on VPg-linked RNA after the initial round of translation in a cell culture model, but both positive and negative strand RNA production is impaired in the absence of TDP2 at mid-times of infection, indicating that the presence of VPg on the viral RNA affects a step in the replication cycle downstream of translation (e.g., RNA synthesis). In agreement with this conclusion, we found that double-stranded RNA production (a marker of viral RNA synthesis) is delayed in TDP2 KO RPE-1 cells. Moreover, we show that premature encapsidation of nascent, VPg-linked RNA is not responsible for the observed virus growth defect. Our studies provide the first lines of evidence to suggest that either negative- or positive-strand RNA synthesis (or both) is a likely candidate for the step that requires the removal of VPg from the RNA for an enterovirus infection to proceed efficiently.

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Diverse Strategies Used by Picornaviruses to Escape Host RNA Decay Pathways

Cited by 21 publications

References 156 publications

Emergency Services of Viral RNAs: Repair and Remodeling

Emergency Services of Viral RNAs: Repair and Remodeling

Identification of phlebovirus and arenavirus RNA sequences that stall and repress the exoribonuclease XRN1

Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation

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