SARS-CoV-2 non-structural protein 13 (nsp13) hijacks host deubiquitinase USP13 and counteracts host antiviral immune response

Guo, Guijie; Gao, Ming; Gao, Xiaohuan; Zhu, Bibo; Huang, Jinzhou; Luo, Kuntian; Zhang, Yong; Sun, Jie; Deng, Min; Lou, Zhenkun

doi:10.1038/s41392-021-00509-3

Cited by 43 publications

(47 citation statements)

References 5 publications

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“…Additionally, nsp13 was shown to play an important role as an innate immune antagonist (Figure 5a). It contributes to the inhibition of the type I interferon response by directly binding to TBK1 and, with that, it impedes IRF3 phosphorylation (Guo et al 2021). The dual role of nsp6 and nsp13 in immune suppression and viral replication may suggest a convergent evolution of SARS-CoV-2 manifested in most of the VOC, which carries either nsp6 Ser 106 _Phe 108 del or nsp13 Asp 260 Tyr.…”

Section: S Pro 681mentioning

confidence: 99%

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Garvin

Prates

Romero

et al. 2021

Preprint

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The SARS-CoV-2 pandemic has entered an alarming new phase with the emergence of the variants of concern (VOC), P.1, B.1.351, and B.1.1.7, in late 2020, and B.1.427, B.1.429, and B.1.617, in 2021. Substitutions in the spike glycoprotein (S), such as Asn501Tyr and Glu484Lys, are likely key in several VOC. However, Asn501Tyr had been circulating for months in earlier strains and Glu484Lys is not found in B.1.1.7, indicating that they do not fully explain those fast-spreading variants. Here we use a computational systems biology approach to process more than 900,000 SARS-CoV-2 genomes and map spatiotemporal relationships, revealing other critical attributes of these variants. Comparisons to earlier dominant mutations and protein structural analyses indicate that the increased transmission is promoted by the combination of functionally complementary mutations in S and in other regions of the SARS-CoV-2 proteome. We report that the VOC have in common mutations in non-S proteins involved in immune-antagonism and replication performance, such as the nonstructural proteins 6 and 13, suggesting a convergent evolution of the virus. Critically, we propose that recombination events among divergent coinfecting haplotypes greatly accelerates the emergence of VOC by bringing together cooperative mutations and explaining the remarkably high mutation load of B.1.1.7. Therefore, extensive community distribution of SARS-CoV-2 increases the probability of future recombination events, further accelerating the evolution of the virus. This study reinforces the need for a global response to stop COVID-19 and future pandemics.

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Section: S Pro 681mentioning

confidence: 99%

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Garvin

Prates

Romero

et al. 2021

Preprint

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“… 10 Some studies have highlighted the importance of nsp13 for its inhibitory role in regulating type I interferon production, as well as the suppression of interferons (IFNs) levels due to nsp13 overexpression via the host USP13. 11 Some recent in silico studies have proposed cepharanthine, idarubicin, and nilotinib as potential inhibitory agents against nsp13. 12 The uridine-specific endoribonuclease nsp15 is highly conserved in the coronavirus family at the C-terminal catalytic domain to recognize uridine moiety, and it is also responsible for the interference of the host immune system.…”

Section: Introductionmentioning

confidence: 99%

Exploring the therapeutic nature of limonoids and triterpenoids against SARS-CoV-2 by targeting nsp13, nsp14, and nsp15 through molecular docking and dynamics simulations

Vardhan

Sahoo

2022

Journal of Traditional and Complementary Medicine

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Background and aim The ongoing global pandemic due to SARS-CoV-2 caused a medical emergency. Since December 2019, the COVID-19 disease is spread across the globe through physical contact and respiratory droplets. Coronavirus caused a severe effect on the human immune system where some of the non-structural proteins (nsp) are involved in virus-mediated immune response and pathogenesis. To suppress the viral RNA replication mechanism and immune-mediated responses, we aimed to identify limonoids and triterpenoids as antagonists by targeting helicases (nsp13), exonuclease (nsp14), and endoribonuclease (nsp15) of SARS-CoV-2 as therapeutic proteins. Experimental procedure In silico molecular docking and drug-likeness of a library of 369 phytochemicals from limonoids and triterpenoids were performed to screen the potential hits that binds effectively at the active site of the proteins target. In addition, the molecular dynamics simulations of the proteins and their complexes with the potential hits were performed for 100 ns by using GROMACS. Results and conclusion The potential compounds 26-deoxyactein and 25-O-anhydrocimigenol 3-O-beta- d -xylopyranoside posing strong interactions with a minimum binding energy of −10.1 and −9.5 kcal/mol, respectively and sustained close contact with nsp13 for 100 ns. The nsp14 replication fork activity was hindered by the tomentosolic acid, timosaponin A-I, and shizukaol A with the binding affinity score of −9.2, −9.2, and −9.0 kcal/mol, respectively. The nsp15 endoribonuclease catalytic residues were inhibited potentially by limonin, 25-O-anhydrocimigenol 3-O-alpha- l -arabinopyranoside, and asperagenin posing strong binding affinity scores of −9.0, −8.8, and −8.7 kcal/mol, respectively. Computationally predicted potential phytochemicals for SARS-CoV-2 are known to possess various medicinal properties.

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“…Moreover, the N protein of PEDV 200 and the NS protein of HRTV 201 inhibit the TBK1/IRF3 interaction by targeting TBK1 directly, while the NS5 protein of Zika virus antagonizes IFN production by blocking TBK1 activation 202 . A recent study demonstrated that NSP13 of SARS-CoV-2 interacts directly with the MAVS binding domain of TBK1 and disrupts the TBK1-MAVS interaction 203 . Membrane-anchored PLpro domain (PLpro-TM) of SARS-CoV inhibits STING/TBK1/IKKε-mediated activation of type I IFNs by disrupting the phosphorylation and dimerization of IRF3 204 .…”

Section: Regulation Of Tbk1 By Rna Viral Proteinsmentioning

confidence: 99%

Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

et al. 2021

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A harmonized balance between positive and negative regulation of pattern recognition receptor (PRR)-initiated immune responses is required to achieve the most favorable outcome for the host. This balance is crucial because it must not only ensure activation of the first line of defense against viral infection but also prevent inappropriate immune activation, which results in autoimmune diseases. Recent studies have shown how signal transduction pathways initiated by PRRs are positively and negatively regulated by diverse modulators to maintain host immune homeostasis. However, viruses have developed strategies to subvert the host antiviral response and establish infection. Viruses have evolved numerous genes encoding immunomodulatory proteins that antagonize the host immune system. This review focuses on the current state of knowledge regarding key host factors that regulate innate immune signaling molecules upon viral infection and discusses evidence showing how specific viral proteins counteract antiviral responses via immunomodulatory strategies.

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SARS-CoV-2 non-structural protein 13 (nsp13) hijacks host deubiquitinase USP13 and counteracts host antiviral immune response

Cited by 43 publications

References 5 publications

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis

Exploring the therapeutic nature of limonoids and triterpenoids against SARS-CoV-2 by targeting nsp13, nsp14, and nsp15 through molecular docking and dynamics simulations

Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing

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