SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response

Liu, Yongzhen; Qin, Chao; Rao, Youliang; Ngo, Chau; Feng, Joshua J; Zhao, Jun; Zhang, Shu; Wang, Ting-Yu; Carrière, Jessica; Savas, Ali Can; Zarinfar, Mehrnaz; Rice, Stephanie; Yang, Hanging; Yuan, Weiming; Camarero, Julio A.; Yu, Jianhua; Chen, Xiaojiang S.; Zhang, Chao; Feng, Pinghui

doi:10.1128/mbio.02335-21

Cited by 91 publications

(91 citation statements)

References 63 publications

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“…2A ) is currently unknown since neither the protease domain nor known interaction interfaces are altered. The other main protease of SARS-CoV-2, Nsp5, targeting the sensor retinoic acid-inducible gene I (RIG-I) and the signal adaptor mitochondrial antiviral-signaling protein (MAVS) known to promote innate immune escape ( 54 , 56 ), has a P132H mutation. This alteration is located neither in the active site nor in the dimerization interface, and its functional consequences remain to be determined.…”

Section: Non-spike Alterations In the Omicron Genomementioning

confidence: 99%

Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?

Jung

Kmieć

Koepke

et al. 2022

J Virol

188

140

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Emerging strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, that show increased transmission fitness and/or immune evasion are classified as “variants of concern” (VOCs). Recently, a SARS-CoV-2 variant first identified in November 2021 in South Africa has been recognized as a fifth VOC, termed “Omicron”. What makes this VOC so alarming is the high number of changes, especially in the viral Spike protein, and accumulating evidence for increased transmission efficiency and escape from neutralizing antibodies. In an amazingly short time, the Omicron VOC has outcompeted the previously dominating Delta VOC. However, it seems that the Omicron VOC is overall less pathogenic compared to other SARS-CoV-2 VOCs. Here, we provide an overview of the mutations in the Omicron genome and the resulting changes in viral proteins compared to other SARS-CoV-2 strains and discuss their potential functional consequences.

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Section: Non-spike Alterations In the Omicron Genomementioning

confidence: 99%

Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?

Jung

Kmieć

Koepke

et al. 2022

J Virol

188

140

View full text Add to dashboard Cite

show abstract

“…Therefore, this protein is a putative target for anticoronavirus therapy. NSP5 may be involved in evading the innate immune response by inhibiting mitochondrial antiviral signalling (MAVS) protein and IFN induction [127]. Mutations in this protein can affect its proteolytic activity.…”

Section: Spike Mutations Aren’t the Only Ones That Mattermentioning

confidence: 99%

Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)

Abbas

Kusakin

Sharrouf

et al. 2022

Preprint

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Aided by extensive protein mutations, the SARS-CoV-2 Omicron (B.1.1.529) variant overtook the previously dominant Delta variant and rapidly spread around the world. It was shown to exhibit significant resistance to current vaccines and evasion from neutralizing antibodies. It is therefore critical to investigate the Omicron mutations trajectories. In this study, a literature search of published articles and SARS-CoV-2 databases was conducted, We explored the full list of mutations in Omicron BA.1, BA.1.1, BA.2, and BA.3 lineages. We described in detail the prevalence and occurrence of the mutations across variants, and how Omicron differs from them. We used GISAID as our primary data source, which provides open access to genomics data of the SARS-CoV-2 virus, in addition to epidemiological and geographical data. We examined how these mutations interact with each other, their co-occurrence and clustering. Our study offers for the first time a comprehensive description of all mutations with a focus on non-spike mutations and demonstrated that mutations in regions other than the Spike (S) genes are worth investigating further. Our research established that the Omicron variant has retained some mutations reported in other SARS-CoV-2 variants, yet many of its mutations are extremely rare in other variants and unique to Omicron. Some of these mutations have been linked to the transmissibility and immune escape of the virus, and indicate a significant shift in SARS-CoV-2 evolution. The most likely theories for the evolution of the Omicron variant were also discussed.

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“…DHX15 mediated sensing of viral RNA activates MAPK and NK-κB innate immune signaling [ 94 ], and also acts as a coreceptor of viral RNA with RIG-I that increases antiviral response and cytokine production [ 95 ]. Interestingly, RIG-I was recently identified as being cleaved by SARS-CoV-2 Nsp5 in vitro [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Predicted coronavirus Nsp5 protease cleavage sites in the human proteome

et al. 2022

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Background The coronavirus nonstructural protein 5 (Nsp5) is a cysteine protease required for processing the viral polyprotein and is therefore crucial for viral replication. Nsp5 from several coronaviruses have also been found to cleave host proteins, disrupting molecular pathways involved in innate immunity. Nsp5 from the recently emerged SARS-CoV-2 virus interacts with and can cleave human proteins, which may be relevant to the pathogenesis of COVID-19. Based on the continuing global pandemic, and emerging understanding of coronavirus Nsp5-human protein interactions, we set out to predict what human proteins are cleaved by the coronavirus Nsp5 protease using a bioinformatics approach. Results Using a previously developed neural network trained on coronavirus Nsp5 cleavage sites (NetCorona), we made predictions of Nsp5 cleavage sites in all human proteins. Structures of human proteins in the Protein Data Bank containing a predicted Nsp5 cleavage site were then examined, generating a list of 92 human proteins with a highly predicted and accessible cleavage site. Of those, 48 are expected to be found in the same cellular compartment as Nsp5. Analysis of this targeted list of proteins revealed molecular pathways susceptible to Nsp5 cleavage and therefore relevant to coronavirus infection, including pathways involved in mRNA processing, cytokine response, cytoskeleton organization, and apoptosis. Conclusions This study combines predictions of Nsp5 cleavage sites in human proteins with protein structure information and protein network analysis. We predicted cleavage sites in proteins recently shown to be cleaved in vitro by SARS-CoV-2 Nsp5, and we discuss how other potentially cleaved proteins may be relevant to coronavirus mediated immune dysregulation. The data presented here will assist in the design of more targeted experiments, to determine the role of coronavirus Nsp5 cleavage of host proteins, which is relevant to understanding the molecular pathology of coronavirus infection.

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SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response

Cited by 91 publications

References 63 publications

Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?

Omicron: What Makes the Latest SARS-CoV-2 Variant of Concern So Concerning?

Follow-up investigation and detailed mutational characterization of the SARS-CoV-2 Omicron variant lineages (BA.1, BA.2, BA.3 and BA.1.1)

Predicted coronavirus Nsp5 protease cleavage sites in the human proteome

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