SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response

Nabeel‐Shah, Syed; Lee, Hyun-Min; Ahmed, Nujhat; Burke, Giovanni L; Farhangmehr, Shaghayegh; Ashraf, Kanwal; Pu, Shuye; Braunschweig, Ulrich; Zhong, Guoqing; Wei, Hong; Tang, Hua; Yang, Jianyi; Marcon, Edyta; Blencowe, Benjamin J.; Zhang, Zhaolei; Greenblatt, Jack

doi:10.1016/j.isci.2021.103562

Cited by 92 publications

(94 citation statements)

References 117 publications

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“…This is similar to what has already been shown for N-mediated disruption of cytoplasmic stress granules, important cytoplasmic biomolecular condensates that correlate with cellular translational shutdown [35]. N protein localizes to stress granules and binds the essential protein, G3BP1, preventing its interaction with other stress granule proteins and blocking stress granule formation [122][123][124]. Although the precise domain required for this effect has been debated, more than one report suggests that the N-terminal intrinsically disordered region is required for stress granule disruption [123,125] .…”

Section: Discussionsupporting

confidence: 85%

“…Second, a possible reason for PB loss may be the indiscriminate binding of RNA by N protein. N protein could be acting as sponge for RNA, pulling it out of cytoplasm, thereby reducing the RNA-protein interactions required for phase separation of PBs [24, 122]. We are currently engaged in site-directed and truncation mutagenesis studies to determine the precise region(s) of SARS-CoV-2-N that is essential for PB disassembly.…”

Section: Discussionmentioning

confidence: 99%

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Human coronaviruses disassemble processing bodies

Robinson

Kleer

Mulloy

et al. 2020

Preprint

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The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Human coronaviruses disassemble processing bodies

Robinson

Kleer

Mulloy

et al. 2020

Preprint

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“…Several coronavirus gene products have been reported to inhibit SG formation. Of these, the most well characterized is the N protein of CoV2 that upon ectopic overexpression, directly binds G3BP1 protein and blocks SG formation induced by variety of exogenous stressors (33)(34)(35). In addition, Nsp15 protein of infectious bronchitis virus (IBV) was shown to inhibit SG formation (17).…”

Section: Introductionmentioning

confidence: 99%

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Dolliver

Kleer

Bui-Marinos

et al. 2022

Preprint

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Stress granules (SGs) are cytoplasmic condensates that often form as part of the cellular antiviral response. Despite the growing interest in understanding the interplay between SGs and other biological condensates and viral replication, the role of SG formation during coronavirus infection remains poorly understood. Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells. To better understand SG inhibition by coronaviruses, we analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the highly pathogenic SARS-CoV2. We did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress (e.g. sodium arsenite treatment). Furthermore, in SARS-CoV2 infected cells we observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and non-structural protein 1 (Nsp1) from both HCoV-OC43 and SARS-CoV-2 inhibited SG formation. The Nsp1 proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause decrease in G3BP1 levels. This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear retention of the SG-nucleating protein TIAR. To test the role of G3BP1 in coronavirus replication, we infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in infection compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.

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“…RNA degradation plays an important role in the reconstruction of mRNA pools in infected cells, and these mRNA pools are mainly dominated by SARS-CoV-2 ( 29 ). A recent study showed that the N protein directly binds to host mRNAs in the cell, and it is preferable to select 3’ UTR and regulate the stability of the target mRNA ( 126 ). Like other viruses, SARS-CoV-2 can hijack the miRNA pathway by producing its own miRNAs, such as CoV2-miR-O7a (SARS-CoV-2 miRNA-like ORF7a-derived small RNA) associates with human Argonaute proteins and represses human targets ( 127 – 129 ).…”

Section: Sars-cov-2 Suppresses Host Protein Translationmentioning

confidence: 99%

Translational Control of COVID-19 and Its Therapeutic Implication

et al. 2022

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, which has broken out worldwide for more than two years. However, due to limited treatment, new cases of infection are still rising. Therefore, there is an urgent need to understand the basic molecular biology of SARS-CoV-2 to control this virus. SARS-CoV-2 replication and spread depend on the recruitment of host ribosomes to translate viral messenger RNA (mRNA). To ensure the translation of their own mRNAs, the SARS-CoV-2 has developed multiple strategies to globally inhibit the translation of host mRNAs and block the cellular innate immune response. This review provides a comprehensive picture of recent advancements in our understanding of the molecular basis and complexity of SARS-CoV-2 protein translation. Specifically, we summarize how this viral infection inhibits host mRNA translation to better utilize translation elements for translation of its own mRNA. Finally, we discuss the potential of translational components as targets for therapeutic interventions.

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SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response

Cited by 92 publications

References 117 publications

Human coronaviruses disassemble processing bodies

Human coronaviruses disassemble processing bodies

Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation

Translational Control of COVID-19 and Its Therapeutic Implication

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