SARS-CoV ORF1b-encoded nonstructural proteins 12–16: Replicative enzymes as antiviral targets

Subissi, Lorenzo; Imbert, Isabelle; Ferrón, François; Collet, Axelle; Coutard, Bruno; Decroly, Étienne; Canard, Bruno

doi:10.1016/j.antiviral.2013.11.006

Cited by 176 publications

(187 citation statements)

References 83 publications

(93 reference statements)

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“…So far, out of the four necessary activities involved in mRNA capping, three were identified in the CoV ORF1b (Figs. 1 and 4) (Subissi et al, 2014a). Current knowledge regarding the 4 steps of cap formation is more fully described in Sections 5.1-5.4.…”

Section: Coronavirus Cap Formation Pathwaymentioning

confidence: 99%

Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus

et al. 2014

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The successive emergence of highly pathogenic coronaviruses (CoVs) such as the Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in 2012 has stimulated a number of studies on the molecular biology. This research has provided significant new insight into functions and activities of the replication/transcription multi-protein complex. The latter directs both continuous and discontinuous RNA synthesis to replicate and transcribe the large coronavirus genome made of a single-stranded, positive-sense RNA of ∼30 kb. In this review, we summarize our current understanding of SARS-CoV enzymes involved in RNA biochemistry, such as the in vitro characterization of a highly active and processive RNA polymerase complex which can associate with methyltransferase and 3'-5' exoribonuclease activities involved in RNA capping, and RNA proofreading, respectively. The recent discoveries reveal fascinating RNA-synthesizing machinery, highlighting the unique position of coronaviruses in the RNA virus world.

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Section: Coronavirus Cap Formation Pathwaymentioning

confidence: 99%

Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus

et al. 2014

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“…in Sections 8 and 11 in more detail). Imaging and biochemical characterization of nidovirus nsps have shown that they are targeted to specific virus-induced membrane structures (reviewed in (Hagemeijer et al, 2012;Neuman et al, 2014;van der Hoeven et al, 2016)) where they assemble into a so-called replication and transcription complex (RTC; see (Neuman et al, 2014;Snijder et al, 2016;Subissi et al, 2014a) for reviews).…”

Section: Introductionmentioning

confidence: 99%

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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“…Based on this parallel, nidoviruses are expected to encode all components of the enzymatic capping machinery which has not been demonstrated yet for any nidovirus. For coronaviruses, a guanylyltransferase has not been identified (Subissi et al, 2014a), while two other major nidovirus groups lack also orthologs of the coronavirus N-MT (toroviruses) or N-MT and O-MT (arteriviruses) (Nga et al, 2011). Thus, the RNA 5 -triphosphatase activity of the helicase protein may be the only enzymatic activity of the capping machinery that is conserved across nidoviruses.…”

Section: Helicase and Translationmentioning

confidence: 99%

What we know but do not understand about nidovirus helicases

et al. 2015

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Helicases are versatile NTP-dependent motor proteins of monophyletic origin that are found in all kingdoms of life. Their functions range from nucleic acid duplex unwinding to protein displacement and double-strand translocation. This explains their participation in virtually every metabolic process that involves nucleic acids, including DNA replication, recombination and repair, transcription, translation, as well as RNA processing. Helicases are encoded by all plant and animal viruses with a positive-sense RNA genome that is larger than 7 kb, indicating a link to genome size evolution in this virus class. Viral helicases belong to three out of the six currently recognized superfamilies, SF1, SF2, and SF3. Despite being omnipresent, highly conserved and essential, only a few viral helicases, mostly from SF2, have been studied extensively. In general, their specific roles in the viral replication cycle remain poorly understood at present. The SF1 helicase protein of viruses classified in the order Nidovirales is encoded in replicase open reading frame 1b (ORF1b), which is translated to give rise to a large polyprotein following a ribosomal frameshift from the upstream ORF1a. Proteolytic processing of the replicase polyprotein yields a dozen or so mature proteins, one of which includes a helicase. Its hallmark is the presence of an N-terminal multi-nuclear zinc-binding domain, the nidoviral genetic marker and one of the most conserved domains across members of the order. This review summarizes biochemical, structural, and genetic data, including drug development studies, obtained using helicases originating from several mammalian nidoviruses, along with the results of the genomics characterization of a much larger number of (putative) helicases of vertebrate and invertebrate nidoviruses. In the context of our knowledge of related helicases of cellular and viral origin, it discusses the implications of these results for the protein's emerging critical function(s) in nidovirus evolution, genome replication and expression, virion biogenesis, and possibly also post-transcriptional processing of viral RNAs. Using our accumulated knowledge and highlighting gaps in our data, concepts and approaches, it concludes with a perspective on future research aimed at elucidating the role of helicases in the nidovirus replication cycle.

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SARS-CoV ORF1b-encoded nonstructural proteins 12–16: Replicative enzymes as antiviral targets

Cited by 176 publications

References 83 publications

Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus

Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

What we know but do not understand about nidovirus helicases

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