Translational control of coronaviruses

Breyne, Sylvain de; Vindry, Caroline; Guillin, Olivia; Condé, Lionel; Mure, Fabrice; Gruffat, Henri; Chavatte, Laurent; Ohlmann, Théophile

doi:10.1093/nar/gkaa1116

Cited by 51 publications

(58 citation statements)

References 236 publications

(274 reference statements)

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“…Firstly, this protein contains conserved cross-reactive T cell epitopes that are present among different coronaviruses, suggesting that it could be a target for universal coronavirus vaccines 26 . Secondly, the nucleocapsid protein is among the most abundant structural proteins in the coronavirus lifecycle 27–29 , which may facilitate antigen presentation and recognition by T cells.…”

Section: Discussionmentioning

confidence: 99%

A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination

Class

Dangi

Richner

et al. 2021

Preprint

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The SARS CoV-2 pandemic has killed millions of people. This viral infection can also result in substantial morbidity, including respiratory insufficiency and neurological manifestations, such as loss of smell and psychiatric diseases. Most SARS CoV-2 vaccines are based on the spike antigen, and although they have shown extraordinary efficacy at preventing severe lung disease and death, they do not always confer sterilizing immune protection. We performed studies in K18-hACE2 mice to evaluate whether the efficacy of SARS CoV-2 vaccines could be augmented by incorporating nucleocapsid as a vaccine antigen. We vaccinated mice with adenovirus-based vaccines encoding spike antigen alone, nucleocapsid antigen alone, or combined spike and nucleocapsid antigens. Mice were then challenged intranasally with SARS CoV-2, and acute viral loads were quantified at a proximal site of infection (lung) and a distal site of infection (brain). Interestingly, the spike-based vaccine conferred acute protection in the lung, but not in the brain. The spike-based vaccine conferred acute protection in the brain only if combined with the nucleocapsid-based vaccine. These findings suggest that nucleocapsid-specific immunity is important for the distal control of SARS CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.

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Section: Discussionmentioning

confidence: 99%

A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination

Class

Dangi

Richner

et al. 2021

Preprint

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“…37 Coronaviruses, including SARS-CoV-1, initiate translation through a cap-and eIF4F-dependent mechanism. 38 Accordingly, disruption of eIF4E-eIF4G interaction by the small-molecule inhibitor 4E2RCat abolished HCoV-229E replication in a cell-based assay, while host protein synthesis was inhibited only by 40%. 39 Likewise, the eIF4A inhibitor silvestrol inhibited expression of MERS-CoV and HCoV-229E nonstructural proteins and formation of viral transcription complexes.…”

Section: Introductionmentioning

confidence: 94%

“…Coronavirus infection activates the p38 pathway MAP kinase, leading to eIF4E phosphorylation at residue Ser 209 . 38 However, while eIF4E phosphorylation is frequently thought to promote translation, 41 global cellular protein synthesis is attenuated following coronavirus infection. 38 Furthermore, a MAP kinase inhibitor failed to reduce viral translation in SARS-CoV-1-infected cells even though it inhibited MAP kinase-dependent eIF4E phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

“…38 However, while eIF4E phosphorylation is frequently thought to promote translation, 41 global cellular protein synthesis is attenuated following coronavirus infection. 38 Furthermore, a MAP kinase inhibitor failed to reduce viral translation in SARS-CoV-1-infected cells even though it inhibited MAP kinase-dependent eIF4E phosphorylation. 42 Thus, the role of eIF4E phosphorylation specifically in coronavirus translation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Single-Molecule Dynamics of SARS-CoV-2 5’ Cap Recognition by Human eIF4F

Hong

Lin

et al. 2021

Preprint

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Coronaviruses initiate translation through recognition of the viral RNA 5′ m7GpppAm cap by translation factor eIF4F. eIF4F is a heterotrimeric protein complex with cap-binding, RNA-binding, and RNA helicase activities. Modulating eIF4F function through cellular regulation or small-molecule inhibition impacts coronavirus replication, including for SARS-CoV-2. Translation initiation involves highly coordinated dynamics of translation factors with messenger or viral RNA. However, how the eIF4F subunits coordinate on the initiation timescale to define cap-binding efficiency remains incompletely understood. Here we report that translation supported by the SARS-CoV-2 5′ UTR is highly sensitive to eIF4A inhibition by rocaglamide. Through a single-molecule fluorescence approach that reports on eIF4E-cap interaction, we dissect how eIF4F subunits contribute to cap-recognition efficiency on the SARS-CoV-2 5′ UTR. We find that free eIF4A enhances cap accessibility for eIF4E binding, but eIF4G alone does not change the kinetics of eIF4E-RNA interaction. Conversely, formation of the full eIF4F complex significantly alters eIF4E-cap interaction, suggesting that coordinated eIF4E and eIF4A activities establish the net eIF4F-cap recognition efficiency. Moreover, the eIF4F complex formed with phosphomimetic eIF4E(S209D) binds the viral UTR more efficiently than with wild-type eIF4E. These results highlight a dynamic interplay of eIF4F subunits and mRNA that determines cap-recognition efficiency.

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“…Such RTCs are composed by a network of interconnected double membrane vesicles (DMV) derived from endoplasmic reticulum [6][7][8] . The role of these vesicles is not fully understood but, certainly, they provide a protected niche for preventing the exposure of viral replication intermediates, such as negative-stranded templates and dsRNAs, to cytosolic innate immune sensors, nucleases and, in general, antiviral host counteractions [9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 evasion from ADAR hyper-editing is both genome-encoded and sustained by the virus replication strategy

Bortoletto

Venier

Shapiro

et al. 2021

Preprint

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SARS-CoV-2 is threatening the human society because of its capability to subvert antiviral defenses, causing cytokine hyper-activation and prolonged damage in multiple tissues with unpredictable outcomes in the mid-long term. Here, we evaluated the role of ADAR, an interferon-stimulated gene able to control the activation of the immune system and to directly modify exogenous dsRNAs, during in-vivo infection by SARS-CoV-2. After accurate analysis of 863 RNA-seq samples from different species, we identified ADAR-mediated hyper-editing of SARS-CoV-2 only in 49 human datasets at a low level (0.036‰ hyper edited reads on average) and preferentially on ORF6. Conversely, in mouse datasets we found abundant hyper-editing of viral reads (up to 1.16‰). The analysis of dinucleotide frequency along the ORFs of α, β, δ and γ coronaviruses highlighted the evolutionary pressure of ADAR enzymes, suggesting that the SARS-CoV-2 resistance to hyper-editing is both genome-encoded and supported by the viral transcription strategy.

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Translational control of coronaviruses

Cited by 51 publications

References 236 publications

A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination

A SARS CoV-2 nucleocapsid vaccine protects against distal viral dissemination

Single-Molecule Dynamics of SARS-CoV-2 5’ Cap Recognition by Human eIF4F

SARS-CoV-2 evasion from ADAR hyper-editing is both genome-encoded and sustained by the virus replication strategy

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