Does form meet function in the coronavirus replicative organelle?

Neuman, Benjamin W.; Angelini, Megan M.; Buchmeier, Michael J.

doi:10.1016/j.tim.2014.06.003

Cited by 41 publications

(47 citation statements)

References 77 publications

(57 reference statements)

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“…A possible model proposes that DMVs may be the initial sites of active RNA synthesis early in infection, whereas at later times, after membrane connections are lost, RNA synthesis shifts to the CMs, and DMVs become end-stage products that sequester nonfunctional dsRNAs to prevent the stimulation of the innate immune response (51, 52). …”

Section: Role Of Double-membrane Vesiclesmentioning

confidence: 99%

Continuous and Discontinuous RNA Synthesis in Coronaviruses

et al. 2015

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Replication of the coronavirus genome requires continuous RNA synthesis, whereas transcription is a discontinuous process unique among RNA viruses. Transcription includes a template switch during the synthesis of subgenomic negative-strand RNAs to add a copy of the leader sequence. Coronavirus transcription is regulated by multiple factors, including the extent of base-pairing between transcription-regulating sequences of positive and negative polarity, viral and cell protein–RNA binding, and high-order RNA-RNA interactions. Coronavirus RNA synthesis is performed by a replication-transcription complex that includes viral and cell proteins that recognize cis-acting RNA elements mainly located in the highly structured 5′ and 3′ untranslated regions. In addition to many viral nonstructural proteins, the presence of cell nuclear proteins and the viral nucleocapsid protein increases virus amplification efficacy. Coronavirus RNA synthesis is connected with the formation of double-membrane vesicles and convoluted membranes. Coronaviruses encode proofreading machinery, unique in the RNA virus world, to ensure the maintenance of their large genome size.

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Section: Role Of Double-membrane Vesiclesmentioning

confidence: 99%

Continuous and Discontinuous RNA Synthesis in Coronaviruses

et al. 2015

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“…Whereas the enzyme is highly active and displays only very limited substrate specificity in vitro (Ivanov et al, 2004a;Nedialkova et al, 2009), it may be confined to a specific compartment in the infected cell and/or its activity may be modulated by interactions with other nsps or host factors. Such differences between in vitro and in vivo activities will surely emerge for other nsps as well, and they may be better understood following the further characterization (including their lipid composition) of the membranous replication organelles with which the metabolically active CoV RTC presumably is associated (Hagemeijer et al, 2012;Neuman et al, 2014a;van der Hoeven et al, 2016). These studies should also answer the question of how both nsps and viral RNA substrates are targeted to or recruited by the membrane-bound CoV RTC, in particular also during the earlier stages of infection when viral RNA synthesis appears to be taking off in the absence of the prominent membrane rearrangements observed later in infection.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

“…As for other +RNA viruses, they have been postulated to serve as scaffolds, or perhaps even suitable microenvironments, for viral RNA synthesis. Nevertheless, many questions on their biogenesis and function remain to be answered, and the exact location of the metabolically active RTC still has to be pinpointed "beyond reasonable doubt" for CoVs and other nidoviruses (Hagemeijer et al, 2012;Neuman et al, 2014a;van der Hoeven et al, 2016). Three ORF1a-encoded replicase subunits containing transmembrane domains (nsp3, nsp4, and nsp6; Fig.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to actively engaging in host membrane remodeling, they may serve as membrane anchors for the RTC by binding the nsps that lack hydrophobic domains, like all of the ORF1b-encoded enzymes. For more details, the reader is referred to the numerous recent reviews of the "replication organelles" of CoVs and other +RNA viruses (den Boon and Ahlquist, 2010;Hagemeijer et al, 2012;Neuman et al, 2014a;Romero-Brey and Bartenschlager, 2016;van der Hoeven et al, 2016;Xu and Nagy, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

Snijder

Decroly

Ziebuhr

2016

Advances in Virus Research

534

620

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Coronaviruses are animal and human pathogens that can cause lethal zoonotic infections like SARS and MERS. They have polycistronic plus-stranded RNA genomes and belong to the order Nidovirales, a diverse group of viruses for which common ancestry was inferred from the common principles underlying their genome organization and expression, and from the conservation of an array of core replicase domains, including key RNA-synthesizing enzymes. Coronavirus genomes (~26-32 kilobases) are the largest RNA genomes known to date and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases. The primary functions that direct coronavirus RNA synthesis and processing reside in nonstructural protein (nsp) 7 to nsp16, which are cleavage products of two large replicase polyproteins translated from the coronavirus genome. Significant progress has now been made regarding their structural and functional characterization, stimulated by technical advances like improved methods for bioinformatics and structural biology, in vitro enzyme characterization, and site-directed mutagenesis of coronavirus genomes. Coronavirus replicase functions include more or less universal activities of plus-stranded RNA viruses, like an RNA polymerase (nsp12) and helicase (nsp13), but also a number of rare or even unique domains involved in mRNA capping (nsp14, nsp16) and fidelity control (nsp14). Several smaller subunits (nsp7-nsp10) act as crucial cofactors of these enzymes and contribute to the emerging "nsp interactome." Understanding the structure, function, and interactions of the RNA-synthesizing machinery of coronaviruses will be key to rationalizing their evolutionary success and the development of improved control strategies.

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“…A key feature of immune evasion by +RNA viruses, and simultaneously the hallmark of +RNA virus infection, is rearrangement of host membranes into viral replication organelles (ROs). As these structures are thought to shield viral RNA from the host innate immune system and additionally seem to play a fundamental role in viral RNA replication, ROs in this sense seem to have a central and dual function in viral replication [10][11][12][13][14]. Therefore, disrupting integrity of ROs might simultaneously result in impaired viral replication and enhanced antiviral immune signaling, which would be a beneficial effect from an antiviral immunity point-of-view.…”

Section: Introductionmentioning

confidence: 99%

Interaction of the innate immune system with positive-strand RNA virus replication organelles

Scutigliani

Kikkert

2017

Cytokine & Growth Factor Reviews

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The potential health risks associated with (re-)emerging positive-strand RNA (+RNA) viruses emphasizes the need for understanding host-pathogen interactions for these viruses. The innate immune system forms the first line of defense against pathogenic organisms like these and is responsible for detecting pathogen-associated molecular patterns (PAMPs). Viral RNA is a potent inducer of antiviral innate immune signaling, provoking an antiviral state by directing expression of interferons (IFNs) and pro-inflammatory cytokines. However, +RNA viruses developed various methods to avoid detection and downstream signaling, including isolation of viral RNA replication in membranous viral replication organelles (ROs). These structures therefore play a central role in infection, and consequently, loss of RO integrity might simultaneously result in impaired viral replication and enhanced antiviral signaling. This review summarizes the first indications that the innate immune system indeed has tools to disrupt viral ROs and other non- or aberrant-self membrane structures, and may do this by marking these membranes with proteins such as microtubule-associated protein 1A/1B-light chain 3 (LC3) and ubiquitin, resulting in the recruitment of IFN-inducible GTPases. Further studies should evaluate whether this process forms a general effector mechanism in +RNA virus infection, thereby creating the opportunity for development of novel antiviral therapies.

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Does form meet function in the coronavirus replicative organelle?

Cited by 41 publications

References 77 publications

Continuous and Discontinuous RNA Synthesis in Coronaviruses

Continuous and Discontinuous RNA Synthesis in Coronaviruses

The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

Interaction of the innate immune system with positive-strand RNA virus replication organelles

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