Targeting of viral RNAs by Upf1-mediated RNA decay pathways

May, Jared; Simon, Anne

doi:10.1016/j.coviro.2020.11.002

Cited by 25 publications

(15 citation statements)

References 110 publications

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“…Two functional polymerase interactors, eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1) and up-frameshift protein 1 (UPF1), are key components of the cellular nonsense mRNA decay (NMD) pathway. UPF1 restricts infection by multiple RNA viruses (May and Simon, 2021), whereas GSPT1, also a translation termination factor (Zhouravleva et al, 1995), has not been implicated in viral infections. Thus, as a proof-of-principle, we examined the role GSPT1 on EBOV infection.…”

Section: Resultsmentioning

confidence: 99%

“…Two functional polymerase interactors, UPF1 and GSPT1, are both key components of the cellular nonsense mRNA decay (NMD) pathway. UPF1 restricts infection by multiple RNA viruses (May and Simon, 2021), whereas GSPT1 has not been implicated in viral infections. Thus, as a proof-of-principle, we focused on GSPT1, which is a translation termination factor that is also termed eRF3a, eukaryotic peptide chain release factor GTP-binding subunit (Zhouravleva et al, 1995).…”

Section: Effect Of Sirna Targeting High-confidence Ebov Polymerase Interactors On Viralmentioning

confidence: 99%

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Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

Fang

Pietzsch

Tsaprailis³

et al. 2021

Preprint

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Ebola virus (EBOV) critically depends on the viral polymerase to replicate and transcribe the viral RNA genome. To examine whether interactions between EBOV polymerase and cellular and viral factors affect distinct viral RNA synthesis events, we applied proximity proteomics to define the cellular interactome of EBOV polymerase, under conditions that recapitulate viral transcription and replication. We engineered EBOV polymerase tagged with the split-biotin ligase split-TurboID, which successfully biotinylated the proximal proteome while retaining polymerase activity. We further analyzed the interactomes in an siRNA-based, functional screen and uncovered 35 host factors, which, when depleted, affect EBOV infection. We validated one host factor, eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we show physically and functionally associates with EBOV polymerase to facilitate viral transcription termination. Our work demonstrates the utility of proximity proteomics to capture the functional host-interactome of the EBOV polymerase and to illuminate host-dependent regulations of viral RNA synthesis.

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Section: Resultsmentioning

confidence: 99%

Section: Effect Of Sirna Targeting High-confidence Ebov Polymerase Interactors On Viralmentioning

confidence: 99%

Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

Fang

Pietzsch

Tsaprailis³

et al. 2021

Preprint

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“…Human G3BP1 can bind and promote the degradation of mRNAs with structured 3’ untranslated regions (3’ UTRs) in conjunction with upframeshift 1 (Upf1) as part of the structure-mediated RNA decay (SRD) pathway [ 75 ]. PEMV2 contains a highly structured 3’ UTR [ 76 ] and like many RNA viruses is inhibited by Upf1 [ 77 , 78 ]. Therefore, G3BP over-expression could enhance SRD targeting of PEMV2 RNAs.…”

Section: Discussionmentioning

confidence: 99%

Phase separation of a plant virus movement protein and cellular factors support virus-host interactions

2021

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Both cellular and viral proteins can undergo phase separation and form membraneless compartments that concentrate biomolecules. The p26 movement protein from single-stranded, positive-sense Pea enation mosaic virus 2 (PEMV2) separates into a dense phase in nucleoli where p26 and related orthologues must interact with fibrillarin (Fib2) as a pre-requisite for systemic virus movement. Using in vitro assays, viral ribonucleoprotein complexes containing p26, Fib2, and PEMV2 genomic RNAs formed droplets that may provide the basis for self-assembly in planta. Mutating basic p26 residues (R/K-G) blocked droplet formation and partitioning into Fib2 droplets or the nucleolus and prevented systemic movement of a Tobacco mosaic virus (TMV) vector in Nicotiana benthamiana. Mutating acidic residues (D/E-G) reduced droplet formation in vitro, increased nucleolar retention 6.5-fold, and prevented systemic movement of TMV, thus demonstrating that p26 requires electrostatic interactions for droplet formation and charged residues are critical for nucleolar trafficking and virus movement. p26 readily partitioned into stress granules (SGs), which are membraneless compartments that assemble by clustering of the RNA binding protein G3BP following stress. G3BP is upregulated during PEMV2 infection and over-expression of G3BP restricted PEMV2 RNA accumulation >20-fold. Deletion of the NTF2 domain that is required for G3BP condensation restored PEMV2 RNA accumulation >4-fold, demonstrating that phase separation enhances G3BP antiviral activity. These results indicate that p26 partitions into membraneless compartments with either proviral (Fib2) or antiviral (G3BP) factors.

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“…[41] Thus, viral proteins that inhibit NMD mechanisms are likely to benefit viral replication. This hypothesis has received experimental evidence from studies done, for example, on human and animal coronaviruses, hepatitis C virus, West Nile, Dengue, Semliki Forest, Zika or human Tlymphotrophic type 1, viruses (reviewed in [1][2][3]).…”

Section: Viruses Fight Nmdmentioning

confidence: 99%

Unusual SMG suspects recruit degradation enzymes in nonsense‐mediated mRNA decay

Gilbert

Saveanu

2022

BioEssays

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Degradation of eukaryotic RNAs that contain premature termination codons (PTC) during nonsense‐mediated mRNA decay (NMD) is initiated by RNA decapping or endonucleolytic cleavage driven by conserved factors. Models for NMD mechanisms, including recognition of PTCs or the timing and role of protein phosphorylation for RNA degradation are challenged by new results. For example, the depletion of the SMG5/7 heterodimer, thought to activate RNA degradation by decapping, leads to a phenotype showing a defect of endonucleolytic activity of NMD complexes. This phenotype is not correlated to a decreased binding of the endonuclease SMG6 with the core NMD factor UPF1, suggesting that it is the result of an imbalance between active (e.g., in polysomes) and inactive (e.g., in RNA‐protein condensates) states of NMD complexes. Such imbalance between multiple complexes is not restricted to NMD and should be taken into account when establishing causal links between gene function perturbation and observed phenotypes.

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Targeting of viral RNAs by Upf1-mediated RNA decay pathways

Cited by 25 publications

References 110 publications

Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

Functional interactomes of the Ebola virus polymerase identified by proximity proteomics in the context of viral replication

Phase separation of a plant virus movement protein and cellular factors support virus-host interactions

Unusual SMG suspects recruit degradation enzymes in nonsense‐mediated mRNA decay

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