Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation

Hosmillo, Myra; Jia, Lianshun; McAllaster, Michael R.; Eaglesham, J.B.; Wang, Xinjie; Emmott, Edward; Domingues, Patricia; Chaudhry, Yasmin; Fitzmaurice, Tim J.; Tung, Matthew K.H.; Panas, Marc D.; McInerney, Gerald M.; Locker, Nicolas; Wilen, Craig B.; Goodfellow, Ian

doi:10.7554/elife.46681

Cited by 54 publications

(49 citation statements)

References 75 publications

(131 reference statements)

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“…Finally, the time-dependent increasing recruitment of a fraction of the available cellular G3BP1 concomitant with the accumulation of viral products in the RC ( Fig 5A) thus evokes the hijacking of this factor by a stoichiometric type of interaction with either viral proteins or nucleic acids and supports the concept that G3BP1 recruitment to MNV RC is required during the viral life cycle. This is further supported by recent evidence that G3BP1 promotes translation of the VPg-linked RNA and is required for replication of MNV and human norovirus [89].…”

Section: Discussionsupporting

confidence: 67%

“…Studies aiming at the discovery of the host factors required for MNV replication in murine macrophages cell line BV2 by CRISPR screening showed the requirement of G3BP1 for MNVinduced cell toxicity and replication, suggesting a viral repurpose of this host anti-viral factor [36,89]. In the present work, we have observed an unexpected spatio-temporal colocalisation of G3BP1 granules with MNV replication complexes by confocal microscopy (Figs 4A and 5A) and a molecular interaction between G3BP1 and viral factor by immunoprecipitation ( Fig 5B).…”

Section: Discussionmentioning

confidence: 99%

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Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation

et al. 2020

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Viral infections impose major stress on the host cell. In response, stress pathways can rapidly deploy defence mechanisms by shutting off the protein synthesis machinery and triggering the accumulation of mRNAs into stress granules to limit the use of energy and nutrients. Because this threatens viral gene expression, viruses need to evade these pathways to propagate. Human norovirus is responsible for gastroenteritis outbreaks worldwide. Here we examined how norovirus interacts with the eIF2α signaling axis controlling translation and stress granules. While norovirus infection represses host cell translation, our mechanistic analyses revealed that eIF2α signaling mediated by the stress kinase GCN2 is uncoupled from translational stalling. Moreover, infection results in a redistribution of the RNA-binding protein G3BP1 to replication complexes and remodelling of its interacting partners, allowing the avoidance from canonical stress granules. These results define novel strategies by which norovirus undergo efficient replication whilst avoiding the host stress response and manipulating the G3BP1 interactome.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation

et al. 2020

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“…Murine norovirus inhibits the formation of canonical SGs not only by redistributing G3BP1 together with the NS3 protein to sites of viral replication, but also by modifying the interactome of G3BP1 [304]. Notably, G3BP1 is directly involved in translation of the norovirus genome by associating with the VPg viral cap complex to help ribosome recruitment [305].…”

Section: G3bp1 At the Interface Between Sgs And The Ifn Responsementioning

confidence: 99%

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Eiermann

Haneke

Sun

et al. 2020

Viruses

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Cells have evolved highly specialized sentinels that detect viral infection and elicit an antiviral response. Among these, the stress-sensing protein kinase R, which is activated by double-stranded RNA, mediates suppression of the host translation machinery as a strategy to limit viral replication. Non-translating mRNAs rapidly condensate by phase separation into cytosolic stress granules, together with numerous RNA-binding proteins and components of signal transduction pathways. Growing evidence suggests that the integrated stress response, and stress granules in particular, contribute to antiviral defense. This review summarizes the current understanding of how stress and innate immune signaling act in concert to mount an effective response against virus infection, with a particular focus on the potential role of stress granules in the coordination of antiviral signaling cascades.

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“…It has become increasingly clear that interactions of vRNAs with proteins play key roles in multiple aspects of viral infection, either through the recruitment of host factors essential for viral translation and replication, or as interaction partners for cellular proteins involved in anti-viral responses (Fritzlar et al, 2019;Garcia-Blanco et al, 2016;Hosmillo et al, 2019) . To understand commonalities and differences in how positive-stranded RNA viruses have evolved to interact with their host, we sought to compare the SARS-CoV-2 dataset to our previously generated ChIRP-MS data from the flaviviruses Zika (ZIKV, ZIKV-PRVABC59) and Dengue-2 (DENV, DENV-16681), as well as a human picornavirus, rhinovirus (RV, RV-B14) (Ooi et al, 2019) .…”

Section: Inter-virus Analysis Of Host Factors Reveals Specificity Of mentioning

confidence: 99%

Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection

Flynn

Yasumoto

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a pandemic with growing global mortality. There is an urgent need to understand the molecular pathways required for host infection and anti-viral immunity. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with viral ChIRP-MS data from three other positive-sense RNA viruses defined pan-viral and SARS-CoV-2-specific host interactions. Functional interrogation of these factors with a genome-wide CRISPR screen revealed that the vast majority of viral RNA-binding proteins protect the host from virus-induced cell death, and we identified known and novel anti-viral proteins that regulate SARS-CoV-2 pathogenicity. Finally, our RNA-centric approach demonstrated a physical connection between SARS-CoV-2 RNA and host mitochondria, which we validated with functional and electron microscopy data, providing new insights into a more general virus-specific protein logic for mitochondrial interactions. Altogether, these data provide a comprehensive catalogue of SARS-CoV-2 RNA-host protein interactions, which may inform future studies to understand the mechanisms of viral pathogenesis, as well as nominate host pathways that could be targeted for therapeutic benefit.Highlights· ChIRP-MS of SARS-CoV-2 RNA identifies a comprehensive viral RNA-host protein interaction network during infection across two species· Comparison to RNA-protein interaction networks with Zika virus, dengue virus, and rhinovirus identify SARS-CoV-2-specific and pan-viral RNA protein complexes and highlights distinct intracellular trafficking pathways· Intersection of ChIRP-MS and genome-wide CRISPR screens identify novel SARS-CoV-2-binding proteins with pro- and anti-viral function· Viral RNA-RNA and RNA-protein interactions reveal specific SARS-CoV-2-mediated mitochondrial dysfunction during infection

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Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation

Cited by 54 publications

References 75 publications

Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation

Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Systematic discovery and functional interrogation of SARS-CoV-2 viral RNA-host protein interactions during infection

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