G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral response

Yang, Wei; Ru, Yi; Ren, Jingjing; Bai, Juncui; Wei, Junshu; Fu, Shaozu; Liu, Xiangtao; Li, Dan; Zheng, Haixue

doi:10.1038/s41419-019-2178-9

Cited by 81 publications

(81 citation statements)

References 40 publications

(42 reference statements)

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“…We also found that Orf9b interacts with a mitochondrial import receptor, Tom70, which acts as an essential adaptor linking MAVS to TBK1/IRF3, resulting in the activation of IRF-3 51 . N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms [52][53][54] . Common among coronaviridae is the manipulation of stress granules (SG) and related RNA biology, possibly leading to suppression of stress granules and host translation shutoff 55 .…”

Section: Sars-cov-2 Interacts With Multiple Innate Immune Pathwaysmentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

431

586

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ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

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Section: Sars-cov-2 Interacts With Multiple Innate Immune Pathwaysmentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

431

586

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“…Overexpression of G3BP1 was shown to induce the formation of SGs to which innate immune factors such as PKR, oligoadenylate synthetase (OAS) 2, and RNase L are recruited, which, in turn, promote the production of certain cytokines such as IL-17, MIP-3a/b, and MCP-5 via activation of the NF-κB and JNK pathways [256]. Independently of its role in SG assembly, G3BP1 was also shown to interact with the RNA sensor RIG-I and positively regulates its downstream signaling [306,307], as well as with the DNA sensor cGAS, thereby enhancing IFN-β production [308]. This might be the reason why several members of the Picornaviridae and related viruses have evolved G3BP1-cleaving proteases, as reported for the Leader protein of foot-and-mouth disease virus, Theiler's murine encephalomyelitis virus (TMEV) and mengovirus [280,309,310], the proteinase 3C of poliovirus, coxsackievirus B3 and encephalomyocarditis virus (EMCV) [245,[311][312][313], as well as the 3C-like proteinase NS6 of feline calicivirus [314].…”

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

117

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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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“…Activation of RNase L by 2-5A produces dsRNA intermediates that signal through Rig-I and or MDA5 via mitochondrial adaptor, MAVS (IPS-1) by activating IRF3 that translocates to the nucleus to enhance IFN-β production (46). Various studies have shown that G3BP1 binds to Rig-I to regulate IFN-β production in response to viral RNA and synthetic dsRNA, polyI:C (39, 52, 53). To examine whether G3BP1 participates in RNase L-mediated IFN-β production, we monitored IFN-β promoter activation in WT and G3BP1 KO cells by directly activating RNase L with 2-5A or introducing RNase L-cleaved small RNAs and compared to control small RNAs.…”

Section: Resultsmentioning

confidence: 99%

“…Reduced levels of IFN-β production facilitated higher replication of SeV in both RNase L KO and G3BP1 KO cells with loss of antiviral effect. A recent study suggests that G3BP1 inhibits SeV and VSV replication by suppressing RNF125-mediated ubiquitination of Rig-I resulting in increased Rig-I expression and IFN production (53). These observations suggest that G3BP1 may regulate host response to viral infections at multiple levels by regulating activity of PRRs like Rig-I as well as nucleating avSG formation.…”

Section: Discussionmentioning

confidence: 99%

RNase L amplifies Interferon signaling by inducing PKR-mediated antiviral stress granules

Manivannan

Siddiqui

Malathi

2020

Preprint

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ABSTRACTVirus infection leads to activation of the interferon-induced endoribonuclease, RNase L, which results in degradation of viral and cellular RNAs. Both cellular and viral RNA cleavage products of RNase L bind pattern recognition receptors (PRR) like Retinoic acid-inducible I (Rig-I) and or melanoma differentiation-associated protein 5 (MDA5) to further amplify interferon (IFN) production and antiviral response. Although much is known about the mechanics of ligand binding and PRR activation, how the cells coordinate RNA sensing to signaling response and interferon production remains unclear. We show that RNA cleavage products of RNase L activity induce formation of antiviral stress granule (avSG) by regulating activation of double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), and recruit antiviral proteins Rig-I, PKR, OAS and RNase L to avSG. Biochemical analysis of purified avSG showed interaction of key stress granule protein, G3BP1, with only PKR and Rig-I and not with OAS or RNase L. AvSG assembly during RNase L activation is required for IRF3-mediated IFN production and not IFN signaling or proinflammatory cytokine induction. Consequently, cells lacking avSG formation or RNase L signaling produced less IFN and showed higher susceptibility during Sendai virus infection demonstrating the importance of avSG in RNase L-mediated host defense. During viral infection, we propose a role for RNase L-cleaved RNAs in inducing avSG containing antiviral proteins to provide a platform for efficient interaction of RNA ligands with pattern recognition receptors to enhance IFN production to effectively mount antiviral response.IMPORTANCEDouble-stranded RNAs produced during viral infections serve as pathogen associated molecular patterns (PAMPs) and bind pattern recognition receptors to stimulate IFN production. RNase L is an IFN-regulated endoribonuclease that is activated in virus-infected cells and cleaves single-stranded viral and cellular RNAs. The RNase L-cleaved dsRNAs signal to Rig-like helicases to amplify IFN production. This study identifies a novel role of antiviral stress granules induced by RNase L as an antiviral signaling hub to coordinate the RNA ligands with cognate receptors to mount effective host response during viral infections.

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G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral response

Cited by 81 publications

References 40 publications

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

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

RNase L amplifies Interferon signaling by inducing PKR-mediated antiviral stress granules

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