The molecular virology of coronaviruses

Hartenian, Ella; Nandakumar, Divya; Lari, Abdolaziz Rastegar; Ly, Michael; Tucker, Jessica M.; Glaunsinger, Britt A.

doi:10.1074/jbc.rev120.013930

Cited by 437 publications

(609 citation statements)

References 327 publications

(320 reference statements)

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“…CoV have single-stranded, positive-sense RNA genomes nearly 30 kb in length 6,7 . Upon entry of a virion into human cells, the genomic RNA is released into the cytoplasm where it must hijack human translation machinery to synthesize viral proteins 8 . As the genomic RNA has a 7methylguanosine (m 7 G) cap on the 5'-terminus, viral protein synthesis likely proceeds via a process reminiscent of that which occurs on typical human messenger RNAs (mRNAs) 9 .…”

Section: Sars-cov-2 and The Closely-related Sars-mentioning

confidence: 99%

Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation

Lapointe¹,

Grosely²,

Johnson

et al. 2020

Preprint

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SARS-CoV-2 recently emerged as a human pathogen and is the causative agent of the COVID-19 pandemic. A molecular framework of how the virus manipulates host cellular machinery to facilitate infection remains unclear. Here, we focus on SARS-CoV-2 NSP1, which is proposed to be a virulence factor that inhibits protein synthesis by directly binding the human ribosome. Using extract-based and reconstitution experiments, we demonstrate that NSP1 inhibits translation initiation on model human and SARS-CoV-2 mRNAs. NSP1 also specifically binds to the small (40S) ribosomal subunit, which is required for translation inhibition. Using single-molecule fluorescence assays to monitor NSP1-40S subunit binding in real time, we demonstrate that eukaryotic translation initiation factors (eIFs) modulate the interaction: NSP1 rapidly and stably associates with most ribosomal pre-initiation complexes in the absence of mRNA, with particular enhancement and inhibition by eIF1 and eIF3j, respectively. Using model mRNAs and an inter-ribosomal-subunit FRET signal, we elucidate that NSP1 competes with RNA segments downstream of the start codon to bind the 40S subunit and that the protein is unable to associate rapidly with 80S ribosomes assembled on an mRNA. Collectively, our findings support a model where NSP1 associates with the open head conformation of the 40S subunit to inhibit an early step of translation, by preventing accommodation of mRNA within the entry channel.

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Section: Sars-cov-2 and The Closely-related Sars-mentioning

confidence: 99%

Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation

Lapointe¹,

Grosely²,

Johnson

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The SARS-CoV-2 genome codes for two large overlapping open reading frames in gene 1 (ORF1a and ORF1b) and a variety of structural and nonstructural accessory proteins (Zhou et al, 2020). Upon infection, SARS-CoV-2 hijacks host cell translation machinery to synthesize ORF1a and ORF1b polyproteins that are subsequently proteolytically cleaved into 16 mature non-structural proteins, namely Nsp1 to Nsp16 (Chan et al, 2020a;Hartenian et al, 2020;Zhou et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism

Shi

Wang

Fontana

et al. 2020

Preprint

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SUMMARYThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious virus that underlies the current COVID-19 pandemic. SARS-CoV-2 is thought to disable various features of host immunity and cellular defense. The SARS-CoV-2 nonstructural protein 1 (Nsp1) is known to inhibit host protein translation and could be a target for antiviral therapy against COVID-19. However, how SARS-CoV-2 circumvents this translational blockage for the production of its own proteins is an open question. Here, we report a bipartite mechanism of SARS-CoV-2 Nsp1 which operates by: (1) hijacking the host ribosome via direct interaction of its C-terminal domain (CT) with the 40S ribosomal subunit and (2) specifically lifting this inhibition for SARS-CoV-2 via a direct interaction of its N-terminal domain (NT) with the 5’ untranslated region (5’ UTR) of SARS-CoV-2 mRNA. We show that while Nsp1-CT is sufficient for binding to 40S and inhibition of host protein translation, the 5’ UTR of SARS-CoV-2 mRNA removes this inhibition by binding to Nsp1-NT, suggesting that the Nsp1-NT-UTR interaction is incompatible with the Nsp1-CT-40S interaction. Indeed, lengthening the linker between Nsp1-NT and Nsp1-CT of Nsp1 progressively reduced the ability of SARS-CoV-2 5’ UTR to escape the translational inhibition, supporting that the incompatibility is likely steric in nature. The short SL1 region of the 5’ UTR is required for viral mRNA translation in the presence of Nsp1. Thus, our data provide a comprehensive view on how Nsp1 switches infected cells from host mRNA translation to SARS-CoV-2 mRNA translation, and that Nsp1 and 5’ UTR may be targeted for anti-COVID-19 therapeutics.

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“…COVID-19 was later declared as a pandemic on 11 March 2020 with at least 118,000 cases and 4,000 deaths reported from 114 6 Coronaviruses are non-segmented, single-stranded, positive-sense RNA viruses making them the largest known RNA viruses with a relatively high mutation rate (Corey et al 2020). With genomes of around 30 kilobase (kb), about kb are for non-structural proteins and about kb are for structural proteins (Fehr and Perlman 2015;Hartenian et al 2020). The non-structural proteins are responsible for viral replication and also important in evading the innate immune response from the host (Hartenian et al 2020).…”

Section: Epidemiologymentioning

confidence: 99%

COVID-19 basics and vaccine development with a Canadian perspective

Liu

Chen

2021

Can. J. Microbiol.

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The ongoing coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving situation. New discoveries about COVID-19 and its causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continue to deepen the understanding of this novel disease. As there is currently no COVID-19 specific treatment, isolation is the most effective method to prevent transmission. Moreover, development of a safe and effective COVID-19 vaccine will be instrumental in reinstating pre-COVID-19 conditions. As of July 31, 2020, there are at least 139 vaccine candidates from around the globe are in preclinical evaluation, with another 26 undergoing clinical evaluation. This paper aims to review the basics of COVID-19, including epidemiology, basic biology of SARS-CoV-2, and transmission. We also review COVID-19 vaccine development, including animal models, platforms under development, and vaccine development in Canada.

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The molecular virology of coronaviruses

Cited by 437 publications

References 327 publications

Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation

Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation

SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism

COVID-19 basics and vaccine development with a Canadian perspective

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