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, Nicholas; Willen, Craig B.; Goodfellow, Ian

doi:10.1101/571455

Cited by 5 publications

(8 citation statements)

References 63 publications

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“…In the second model, SARS‐CoV‐2 proteins may induce the formation of unique types of granules, either independently of stress granules or via initial recruitment to but subsequent separation from stress granules. Support for this type of model exists for unrelated viruses, whereby viral proteins actually induce stress granules that differ from canonical stress granules in their molecular composition or co‐opt stress granule components for viral replication or viral mRNA translation 13‐16,41,42 . In the third model, N protein may inhibit the formation of stress granules by physical interaction and sequestration of key stress granule components, including G3BP1, G3BP2, and hnRNPA1.…”

Section: Multiple Distinct Lines Of Evidence Connect the N Protein Wimentioning

confidence: 99%

A proposed role for the SARS‐CoV‐2 nucleocapsid protein in the formation and regulation of biomolecular condensates

2020

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SARS-CoV-2 has recently emerged as the seventh coronavirus known to infect humans. 1 Since its discovery, SARS-CoV-2 has resulted in >6.9 million documented human infections worldwide and >400 000 deaths reported to date, according to the World Health Organization (https://www. who.int/emerg encie s/disea ses/novel-coron aviru s-2019/situa tion-reports; accessed on 6/9/20). Given the magnitude of this ongoing pandemic, a molecular-level understanding of SARS-CoV-2 infection and host interaction is of paramount importance for rational drug development. The nucleocapsid ("N") protein of the closely related SARS-CoV 2,3 is essential for the formation of new virions and is the most common antigen of host-produced antibodies during infection by the closely related SARS-CoV virus, 4 and the SARS-CoV-2 N

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Section: Multiple Distinct Lines Of Evidence Connect the N Protein Wimentioning

confidence: 99%

A proposed role for the SARS‐CoV‐2 nucleocapsid protein in the formation and regulation of biomolecular condensates

2020

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“…3A, Table S6) were enriched in IFNγ-treated and norovirus infected cells compared to mock conditions. Among the targeted genes were G3bp1, Sptcl1 and Sptcl2 which are required for efficient norovirus replication (21, 45–47). Among the genes identified as candidates for enhancing IFNγ-induced inhibition of norovirus replication were Iqgap1 and Ufc1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mock or IFNγ treatment alone revealed genes essential for cell survival, which were not studied further. Analysis of cells treated with IFNγ and infected with norovirus revealed genes essential for efficient norovirus replication (21, 45–47) and the genes that regulate responses to IFNγ such as Ufc1 and Uba5 . We further showed that Wipi2 and Atg9a are required for efficient IFNγ-induced inhibition of norovirus replication; we were able to confirm a role for WIPI2B in control of T. gondii in addition to norovirus replication.…”

Section: Discussionmentioning

confidence: 99%

Autophagy gene-dependent intracellular immunity triggered by interferon-γ

Bhushan

et al. 2021

Preprint

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Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct cellular processes with significant physiologic importance. One of the first-described of these ATG gene-dependent processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of Norovirus and Toxoplasma gondii replication. Herein we identified new genes that are required for or that negatively regulate this immune mechanism. Enzymes involved in the conjugation of UFM1 to target proteins including UFC1 and UBA5, negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. IFNγ-induced inhibition of norovirus replication required Wipi2b and Atg9a, but not Becn1 (encoding Beclin1), Atg14, or Sqstm1. The phosphatidylinositol-3-phosphate and ATG16L1 binding domains of WIPI2B were required for IFNγ-induced inhibition of norovirus replication. Both WIPI2 and SQSTM1 were required for IFN?-induced inhibition of Toxoplasma gondii replication in HeLa cells. These studies further delineate the mechanisms of a programmable form of cytokine-induced intracellular immunity that relies on an expanding cassette of essential ATG genes to restrict the growth of phylogenetically diverse pathogens.

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“…Correlation coefficient was calculated on grouped Polysomal and Total data using the Pearson method in GraphPad. Primers are listed in the supplementary data.Biorthogonal labelling for characterisation of de novo proteome Stable isotope labelling of amino acids in RAW264.7 cells culture was performed as described in(82) and carried out in high-glucose DMEM lacking arginine and lysine (Sigma-Aldrich) supplemented with dialysed 10% FBS, 1% L-Glutamine, 1x NEAA, 10mM HEPES and 1x penicillin/streptomycin. RAW264.7 cells were maintained in SILAC media supplemented with Light (R0K0), Medium (R6K4) or Heavy (R10K8) Arginine and Lysine (Cambridge Isotope Laboratories) for 5 passages, ensuring complete incorporation of the different isotopes.…”

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confidence: 99%

“…Validation IP was performed similarly but the AHA-labelling time was increased to 2 hours to improve labelling and enrichment. Eluted fractions were submitted for mass spectrometry analysis at the University of Bristol Proteomics Facility as described in(82). SILAC pooled samples were run on an SDS-PAGE gel and each gel lane cut into 10 equal slices.…”

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confidence: 99%

Murine Norovirus infection results in anti-inflammatory response downstream of amino acids depletion in macrophages

Brocard

Jia

Hall

et al. 2021

Preprint

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Murine norovirus (MNV) infection results in a late translation shut-off, that is proposed to contribute to the attenuated and delayed innate immune response observed both in vitro and in vivo. Recently, we further demonstrated the activation of the eIF2α kinase GCN2 during MNV infection, which has been previously linked to immunomodulation and resistance to inflammatory signalling during metabolic stress. While viral infection is usually associated with activation of dsRNA binding pattern recognition receptor PKR, we hypothesised that the establishment of a metabolic stress in infected cells is a proviral event, exploited by MNV to promote replication through weakening the activation of the innate immune response. In this study, we used multi-omics approaches to characterise cellular responses during MNV replication. We demonstrate the activation of pathways related to the integrated stress response, a known driver of anti-inflammatory phenotypes in macrophages. In particular, MNV infection causes an amino acid imbalance that is associated with GCN2 and ATF2 signalling. Importantly, this reprogramming lacks the features of a typical innate immune response, with the ATF/CHOP target GDF15 contributing to the lack of antiviral responses. We propose that MNV-induced metabolic stress supports the establishment of host tolerance to viral replication and propagation.ImportanceDuring viral infection, host defences are typically characterised by the secretion of pro-inflammatory autocrine and paracrine cytokines, potentiation of the IFN response and induction of the anti-viral response via activation of JAK and Stat signalling. To avoid these and propagate viruses have evolved strategies to evade or counteract host sensing. In this study, we demonstrate that murine norovirus controls the antiviral response by activating a metabolic stress response that activates the amino acid response and impairs inflammatory signalling. This highlights novel tools in the viral countermeasures tool-kit, and demonstrates the importance of the currently poorly understood metabolic reprogramming occurring during viral infections.

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

Cited by 5 publications

References 63 publications

A proposed role for the SARS‐CoV‐2 nucleocapsid protein in the formation and regulation of biomolecular condensates

A proposed role for the SARS‐CoV‐2 nucleocapsid protein in the formation and regulation of biomolecular condensates

Autophagy gene-dependent intracellular immunity triggered by interferon-γ

Murine Norovirus infection results in anti-inflammatory response downstream of amino acids depletion in macrophages

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