SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Choi, Jung‐Hyun; Dai, David L.; Luo, Jun; Ladak, Reese Jalal; Li, Qian; Wang, Yimeng; Zhang, Christine; Wiebe, Sabrina; Liu, Alex; Ran, Xiaozhuo; Yang, Jiaqi; Naeli, Parisa; Garzia, Aitor; Zhou, Lele; Mahmood, Niaz; Deng, Qiyun; Elaish, Mohamed; Lin, Rongtuan; Mahal, Lara K.; Hobman, Tom C.; Alain, Tommy; Vidal, Silvia M.; Mazhab-Jafari, Mohammad T.; Mao, Xiaodan; Jafarnejad, Seyed Mehdi; Sonenberg, Nahum

doi:10.1073/pnas.2204539119

Cited by 32 publications

(49 citation statements)

References 60 publications

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“…However, these studies offer two contradictory models of how Nsp2-eIF4E2 interaction affects translation initiation of capped mRNAs. According to the Xu et al model, binding of Nsp2 to GIGYF2 enhances the interaction between GIGYF2 and eIF4E2, all bound to the cap-5'-end of mRNA (Xu et al, 2022). In contrast, Zou et al's model suggest that binding of Nsp2 to the eIF4E2-GIGYF2 protein complex prevents its binding to the 5'-end cap-structure (Zou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…It was demonstrated that the eIF4E2-GIGYF2 protein complex is involved in miRNA-mediated translational inhibition and degradation of tristetraprolin-targeted mRNAs (Morita et al ., 2012), (Fu et al, 2016). It was demonstrated that direct binding of Nsp2 to GYGYF2 enhances the formation of 4EHP-GIGYF2 protein complex that inhibits translation of IFN1ß mRNA (Xu et al, 2022). A 1-350aa region of Nsp2 has been identified to be required for binding to eIF4E2-GIGYF2 complex (Zou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Protein Nsp2 Stimulates Translation Under Normal and Hypoxic Conditions

Korneeva

Khalil

Ghosh

et al. 2022

Preprint

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When viruses like SARS-CoV-2 infect cells, they reprogram the repertoire of cellular and viral transcripts that are being translated to optimize their strategy of replication, often targeting host translation initiation factors, particularly eIF4F complex consisting of eIF4E, eIF4G and eIF4A. A proteomic analysis of SARS-CoV-2/human proteins interaction revealed viral Nsp2 and initiation factor eIF4E2, but a role of Nsp2 in regulating translation is unknown. HEK293T cells stably expressing Nsp2 were tested for protein synthesis rates of synthetic and endogenous mRNAs known to be translated via cap- or IRES-dependent mechanism under normal and hypoxic conditions. Both cap- and IRES-dependent translation were increased in Nsp2-expressing cells under normal and hypoxic conditions, especially mRNAs that require high levels of eIF4F. This could be exploited by the virus to maintain high translation rates of both viral and cellular proteins, particularly in hypoxic conditions as may arise in SARS-CoV-2 patients with poor lung functioning.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Protein Nsp2 Stimulates Translation Under Normal and Hypoxic Conditions

Korneeva

Khalil

Ghosh

et al. 2022

Preprint

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“…Previously it has been shown that Nsp2 protein suppresses host immune response by inhibiting the mRNA translation of interferon gene 44 . Although C913U mutation does not alter the amino acid residue of Nsp2 protein, it may be worthwhile to see if this C913U mutation plays a direct or indirect role in host immune response through Nsp2 protein.…”

Section: Identification Of Sars-cov-2 Synonymous Mutationsmentioning

confidence: 99%

Prediction of the effects of the top 10 synonymous mutations from 26645 SARS-CoV-2 genomes

Boon

Sia

2022

F1000Res

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Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had led to a global pandemic since December 2019. SARS-CoV-2 is a single-stranded RNA virus, which mutates at a higher rate. Multiple works had been done to study nonsynonymous mutations, which change protein sequences. However, there is little study on the effects of SARS-CoV-2 synonymous mutations, which may affect viral fitness. This study aims to predict the effect of synonymous mutations on the SARS-CoV-2 genome. Methods: A total of 26645 SARS-CoV-2 genomic sequences retrieved from Global Initiative on Sharing all Influenza Data (GISAID) database were aligned using MAFFT. Then, the mutations and their respective frequency were identified. Multiple RNA secondary structures prediction tools, namely RNAfold, IPknot++ and MXfold2 were applied to predict the effect of the mutations on RNA secondary structure and their base pair probabilities was estimated using MutaRNA. Relative synonymous codon usage (RSCU) analysis was also performed to measure the codon usage bias (CUB) of SARS-CoV-2. Results: A total of 150 synonymous mutations were identified. The synonymous mutation identified with the highest frequency is C3037U mutation in the nsp3 of ORF1a.. Of these top 10 highest frequency synonymous mutations, C913U, C3037U, U16176C and C18877U mutants show pronounced changes between wild type and mutant in all 3 RNA secondary structure prediction tools, suggesting these mutations may have some biological impact on viral fitness. These four mutations show changes in base pair probabilities. All mutations except U16176C change the codon to a more preferred codon, which may result in higher translation efficiency. Conclusion: Synonymous mutations in SARS-CoV-2 genome may affect RNA secondary structure, changing base pair probabilities and possibly resulting in a higher translation rate. However, lab experiments are required to validate the results obtained from prediction analysis.

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“…We recently reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encoded non-structural protein 2 (NSP2) functions as a repressor of cellular mRNA translation via direct binding and stabilisation of the GIGYF2/4EHP complex [22]. However, it is not known whether and how NSP2 affects miRNA-mediated silencing, which also utilises the GIGYF2/4EHP complex for translational repression of target mRNAs.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

Naeli

Snell

Chatterjee

et al. 2023

Preprint

Self Cite

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microRNAs (miRNAs) inhibit mRNA translation initiation by recruiting the GIGYF2/4EHP translation repressor complex to the mRNA 5' cap structure. Viruses utilise miRNAs to impair the host antiviral immune system and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs. We recently reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encoded non-structural protein 2 (NSP2) interacts with GIGYF2. This interaction is critical for blocking translation of the Ifn1-b mRNA that encodes the cytokine Interferon-beta, and thereby impairs the host antiviral immune response. However, it is not known whether NSP2 also affects miRNA-mediated silencing. Here, we demonstrate the pervasive augmentation of the miRNA-mediated translational repression of cellular mRNAs by NSP2. We show that NSP2 interacts with Argonaute 2, the core component of the miRNA-Induced Silencing Complex (miRISC) and enhances the translational repression mediated by natural miRNA binding sites in the 3' UTR of cellular mRNAs. Our data reveal an additional layer of the complex mechanism by which SARS-CoV-2 and likely other coronaviruses manipulate the host gene expression program through co-opting the host miRNA-mediated silencing machinery.

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SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Cited by 32 publications

References 60 publications

SARS-CoV-2 Protein Nsp2 Stimulates Translation Under Normal and Hypoxic Conditions

SARS-CoV-2 Protein Nsp2 Stimulates Translation Under Normal and Hypoxic Conditions

Prediction of the effects of the top 10 synonymous mutations from 26645 SARS-CoV-2 genomes

SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

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