Continuous and Discontinuous RNA Synthesis in Coronaviruses

Sola, Isabel; Almazán, Fernando; Zúñiga, Sonia; Enjuanes, Luis

doi:10.1146/annurev-virology-100114-055218

Cited by 608 publications

(779 citation statements)

References 166 publications

(204 reference statements)

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“…The importance of (−)TRS-(+)TRS base pairing was probed and confirmed extensively by site-directed mutagenesis and reverse genetics for both AVs and CoVs (reviewed in (Pasternak et al, 2006;Sawicki et al, 2007;Sola et al, 2011). In addition to TRS base pairing, higher-order RNA structure likely co-determines the relative efficiency of different TRSs in nidovirus transcription, which mechanistically resembles the process of copy-choice RNA recombination, as it is thought to commonly occur among +RNA viruses (Pasternak et al, 2001;Sola et al, 2015;Yount et al, 2006).…”

Section: Making the Rdrp Switch From Continuous Into Discontinuous Momentioning

confidence: 98%

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

2017

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Coronaviruses and arteriviruses are distantly related human and animal pathogens that belong to the order Nidovirales. Nidoviruses are characterized by their polycistronic plus-stranded RNA genome, the production of subgenomic mRNAs and the conservation of a specific array of replicase domains, including key RNA-synthesizing enzymes. Coronaviruses (26-34 kilobases) have the largest known RNA genomes and their replication presumably requires a processive RNA-dependent RNA polymerase (RdRp) and enzymatic functions that suppress the consequences of the typically high error rate of viral RdRps. The arteriviruses have significantly smaller genomes and form an intriguing package with the coronaviruses to analyse viral RdRp evolution and function. The RdRp domain of nidoviruses resides in a cleavage product of the replicase polyprotein named non-structural protein (nsp) 12 in coronaviruses and nsp9 in arteriviruses. In all nidoviruses, the C-terminal RdRp domain is linked to a conserved N-terminal domain, which has been coined NiRAN (nidovirus RdRp-associated nucleotidyl transferase). Although no structural information is available, the functional characterization of the nidovirus RdRp and the larger enzyme complex of which it is part, has progressed significantly over the past decade. In coronaviruses several smaller, non-enzymatic nsps were characterized that direct RdRp function, while a 3'-to-5' exoribonuclease activity in nsp14 was implicated in fidelity. In arteriviruses, the nsp1 subunit was found to maintain the balance between genome replication and subgenomic mRNA production. Understanding RdRp behaviour and interactions during RNA synthesis and subsequent processing will be key to rationalising the evolutionary success of nidoviruses and the development of antiviral strategies.

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Section: Making the Rdrp Switch From Continuous Into Discontinuous Momentioning

confidence: 98%

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

2017

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“…The 3 0 -third of the genome encodes a series of structural proteins in the order 5 0 -S-E-M-N-3 0 and genus-specific proteins that vary in number among the different CoV members ( Fig. 1) (de Groot et al, 2012;Sola et al, 2015).…”

Section: Cov Genome Structure and Protein Compositionmentioning

confidence: 99%

Molecular Basis of Coronavirus Virulence and Vaccine Development

Enjuanes

Zúñiga

Castaño-Rodríguez

et al. 2016

Advances in Virus Research

149

141

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Virus vaccines have to be immunogenic, sufficiently stable, safe, and suitable to induce long-lasting immunity. To meet these requirements, vaccine studies need to provide a comprehensive understanding of (i) the protective roles of antiviral B and T-cell-mediated immune responses, (ii) the complexity and plasticity of major viral antigens, and (iii) virus molecular biology and pathogenesis. There are many types of vaccines including subunit vaccines, whole-inactivated virus, vectored, and live-attenuated virus vaccines, each of which featuring specific advantages and limitations. While nonliving virus vaccines have clear advantages in being safe and stable, they may cause side effects and be less efficacious compared to live-attenuated virus vaccines. In most cases, the latter induce long-lasting immunity but they may require special safety measures to prevent reversion to highly virulent viruses following vaccination. The chapter summarizes the recent progress in the development of coronavirus (CoV) vaccines, focusing on two zoonotic CoVs, the severe acute respiratory syndrome CoV (SARS-CoV), and the Middle East respiratory syndrome CoV, both of which cause deadly disease and epidemics in humans. The development of attenuated virus vaccines to combat infections caused by highly pathogenic CoVs was largely based on the identification and characterization of viral virulence proteins that, for example, interfere with the innate and adaptive immune response or are involved in interactions with specific cell types, such as macrophages, dendritic and epithelial cells, and T lymphocytes, thereby modulating antiviral host responses and viral pathogenesis and potentially resulting in deleterious side effects following vaccination.

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“…Even though our knowledge on the unique discontinuous transcription of arterivirus and coronavirus has rapidly grown over the last years, the molecular mechanisms controlling template switch still remain unclear (Di et al, 2018;Sola et al, 2015). In coronavirus, RNA helicase DDX1 was reported to benefit the synthesis of longer sgRNAs by unwinding the hairpin loop structure of viral gRNA, implying that RNA secondary structure may hinder the balance between shorter and longer sgRNAs synthesis (Wu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Nucleotide-binding oligomerization domain-like receptor X1 restricts porcine reproductive and respiratory syndrome virus-2 replication by interacting with viral Nsp9

et al. 2019

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Porcine reproductive and respiratory syndrome virus (PRRSV) causes one of the most economically important diseases of swine worldwide. Current antiviral strategies provide only limited protection. Nucleotide-binding oligomerization domain-like receptor (NLR) X1 is unique among NLR proteins in its functions as a pro-viral or antiviral factor to different viral infections. To date, the impact of NLRX1 on PRRSV infection remains unclear. In this study, we found that PRRSV infection promoted the expression of NLRX1 gene. In turn, ectopic expression of NLRX1 inhibited PRRSV replication in Marc-145 cells, whereas knockdown of NLRX1 enhanced PRRSV propagation in porcine alveolar macrophages (PAMs). Mechanistically, NLRX1 was revealed to impair intracellular viral subgenomic RNAs accumulation. Finally, Mutagenic analyses indicated that the LRR (leucine-rich repeats) domain of NLRX1 interacted with PRRSV Nonstructural Protein 9 (Nsp9) RdRp (RNA-dependent RNA Polymerase) domain and was necessary for antiviral activity. Thus, our study establishes the role of NLRX1 as a new host restriction factor in PRRSV infection.

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Continuous and Discontinuous RNA Synthesis in Coronaviruses

Cited by 608 publications

References 166 publications

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

Molecular Basis of Coronavirus Virulence and Vaccine Development

Nucleotide-binding oligomerization domain-like receptor X1 restricts porcine reproductive and respiratory syndrome virus-2 replication by interacting with viral Nsp9

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