The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression

Mendez, Aaron S; Ly, Michael; González-Sánchez, Angélica M.; Hartenian, Ella; Ingolia, Nicholas T.; Cate, J.H.D.; Glaunsinger, Britt A.

doi:10.1016/j.celrep.2021.109841

Cited by 95 publications

(185 citation statements)

References 68 publications

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“…Additionally, Arg124 and Lys125 are not contacting to the ribosome in the model structure, which is consistent to the fact that the UV cross-linking to 18S RNA was unaffected by these two mutations. [15] On the other hand, recently reported Arg99Ala mutation to nsp1, which also lacks the ability to recognize viral RNA, [51] did not match important hydrogen bonds we found in the top clusters. This may be attributed to the insufficient sampling around Arg99 (it is not included in the REST2 region) and/or lack of important binding partners in the system, e.g.…”

Section: Relation To Other Experimental Resultscontrasting

confidence: 75%

“…It has been reported that the Arg124Ala–Lys125Ala double nsp1 mutant lacks the ability to recognize viral RNA. [ 3 , 51 ] This can be explained by the results of our simulation, which showed that sidechain of Arg124 strongly interacts with the phosphate backbone of U18 ( Table 1 and Figs 4 and 9 ). An Arg124Ala mutation would eliminate the ionic interaction between the sidechain and the backbone, and nsp1 would lose its ability to recognize viral RNA.…”

Section: Resultsmentioning

confidence: 73%

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Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

et al. 2022

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Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2’s own RNA evades nsp1’s host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results suggested that the stem loop structure of the SARS-CoV-2 RNA 5’-untranslated region (SL1) binds to both nsp1’s N-terminal globular region and intrinsically disordered region. The consistency of the results was assessed by modeling nsp1-40S ribosome structure based on reported nsp1 experiments, including the X-ray crystallographic structure analysis, the cryo-EM electron density map, and cross-linking experiments. The SL1 binding region predicted from the simulation was open to the solvent, yet the ribosome could interact with SL1. Cluster analysis of the binding mode and detailed analysis of the binding poses suggest residues Arg124, Lys47, Arg43, and Asn126 may be involved in the SL1 recognition mechanism, consistent with the existing mutational analysis.

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Section: Relation To Other Experimental Resultscontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 73%

Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

et al. 2022

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“…The IFNL2-genomic and IFNL2-cDNA reporters were gifts from Dr. Marta Gaglia (Tufts University) [ 22 ]. The expression vectors for B2 SINEs and Adv-VAI were obtained from a prior study in the lab [ 37 ].…”

Section: Methodsmentioning

confidence: 99%

Vaccinia virus D10 has broad decapping activity that is regulated by mRNA splicing

Burgess

Shah

et al. 2022

PLoS Pathog

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The mRNA 5’ cap structure serves both to protect transcripts from degradation and promote their translation. Cap removal is thus an integral component of mRNA turnover that is carried out by cellular decapping enzymes, whose activity is tightly regulated and coupled to other stages of the mRNA decay pathway. The poxvirus vaccinia virus (VACV) encodes its own decapping enzymes, D9 and D10, that act on cellular and viral mRNA, but may be regulated differently than their cellular counterparts. Here, we evaluated the targeting potential of these viral enzymes using RNA sequencing from cells infected with wild-type and decapping mutant versions of VACV as well as in uninfected cells expressing D10. We found that D9 and D10 target an overlapping subset of viral transcripts but that D10 plays a dominant role in depleting the vast majority of human transcripts, although not in an indiscriminate manner. Unexpectedly, the splicing architecture of a gene influences how robustly its corresponding transcript is targeted by D10, as transcripts derived from intronless genes are less susceptible to enzymatic decapping by D10. As all VACV genes are intronless, preferential decapping of transcripts from intron-containing genes provides an unanticipated mechanism for the virus to disproportionately deplete host transcripts and remodel the infected cell transcriptome.

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“…Indeed, Nsp1 C terminus binds to 40S ribosomal subunit and obstructs the mRNA entry tunnel, thereby, blocking antiviral responses triggered by RIG-I [145] . It was also suggested that SARS-CoV-2 Nsp1 prevents mRNA nuclear export through interaction with the host mRNA export receptor heterodimer NXF1-NXT1, which is involved in nuclear export of cellular mRNAs, thereby subsequently suppressing protein synthesis [146] , [147] .…”

Section: Immunoediting In Sars-cov-2mentioning

confidence: 99%

Immunoediting in SARS-CoV-2: Mutual relationship between the virus and the host

Kheshtchin

Bakhshi

Arab

et al. 2022

International Immunopharmacology

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Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es), where the immune system first suppresses the growth of tumor cells and then promotes them towards the malignancy. This phenomenon has been conceptualized in some chronic viral infections such as HTLV-1 and HIV by obtaining the resistance to elimination and making a persistent form of infected cells especially in untreated patients. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a heterogeneous disease characterizing from mild/asymptomatic to severe/critical courses with some behavioral aspects in an immunoediting setting. In this context, a coordinated effort between of innate and adaptive immune system leads to detection and destruction of early infection followed by equilibrium between virus-specific responses and infected cells, which eventually end up with an uncontrolled inflammatory response in severe/critical patients. Although the SARS-CoV-2 applies several escape strategies such as mutations in viral epitopes, modulating the interferon response and inhibiting the MHC I molecules similar to the cancer cells, the 3Es hallmark may not occur in all clinical conditions. Here, we discuss how the lesson learnt from cancer immunoediting and accurate understanding of these pathophysiological mechanisms helps to develop more effective therapeutic strategies for COVID-19.

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The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression

Cited by 95 publications

References 68 publications

Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

Vaccinia virus D10 has broad decapping activity that is regulated by mRNA splicing

Immunoediting in SARS-CoV-2: Mutual relationship between the virus and the host

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