Diverse roles and interactions of RNA structures during the replication of positive-stranded RNA viruses of humans and animals

Tuplin, Andrew

doi:10.1099/vir.0.000066

Cited by 19 publications

(18 citation statements)

References 46 publications

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“…The molecular basis for these data is unclear, but the defects in the mutants might already occur at the RNA level, causing the RNA to adopt an unfavorable structure for translation and/or replication (44,45). Alternatively, the extensive sequence divergence of prM TMDs-which is much higher than that of E TMDs (Fig.…”

Section: Discussionmentioning

confidence: 98%

Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly

Blazevic

Rouha

Bradt

et al. 2016

J Virol

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The structural proteins of flaviviruses carry a unique set of transmembrane domains (TMDs) at their C termini that are derived from the mode of viral polyprotein processing. They function as internal signal and stop-transfer sequences during protein translation, but possible additional roles in protein interactions required during assembly and maturation of viral particles are ill defined. To shed light on the role of TMDs in these processes, we engineered a set of tick-borne encephalitis virus mutants in which these structural elements were replaced in different combinations by the homologous sequences of a distantly related flavivirus (Japanese encephalitis virus). The effects of these modifications were analyzed with respect to protein synthesis, viral particle secretion, specific infectivity, and acidic-pH-induced maturation processes. We provide evidence that interactions involving the double-membrane anchor of the envelope protein E (a unique feature compared to other viral fusion proteins) contribute substantially to particle assembly, stability, and maturation. Disturbances of the inter-and intra-TMD interactions of E resulted in the secretion of a larger proportion of capsidless subviral particles at the expense of whole virions, suggesting a possible role in the still incompletely understood mechanism of capsid integration during virus budding. In contrast, the TMD initially anchoring the C protein to the endoplasmic reticulum membrane does not appear to take part in envelope protein interactions. We also show that E TMDs are involved in the envelope protein rearrangements that are triggered by acidic pH in the trans-Golgi network and represent a hallmark of virus maturation. IMPORTANCEThe assembly of flaviviruses occurs in the endoplasmic reticulum and leads to the formation of immature, noninfectious particles composed of an RNA-containing capsid surrounded by a lipid membrane, with the two integrated envelope proteins, prM and E, arranged in an icosahedral lattice. The mechanism by which the capsid is formed and integrated into the budding viral envelope is currently unknown. We provide evidence that the transmembrane domains (TMDs) of E are essential for the formation of capsid-containing particles and that disturbances of these interactions lead to the preferential formation of capsidless subviral particles at the expense of whole virions. E TMD interactions also appear to be essential for the envelope protein rearrangements required for virus maturation and for the generation of infectious virions. Our data thus provide new insights into the biological functions of E TMDs and extend their role during viral polyprotein processing to additional functions in particle assembly and maturation.T he genus Flavivirus in the family Flaviviridae comprises 53 taxonomically recognized species (1), including the humanpathogenic mosquito-borne dengue, Zika, yellow fever, Japanese encephalitis, and West Nile viruses as well as tick-borne encephalitis virus (TBEV) (2). Flaviviruses are small enveloped po...

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Section: Discussionmentioning

confidence: 98%

Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly

Blazevic

Rouha

Bradt

et al. 2016

J Virol

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“…In addition, the folded architecture of the SARS-CoV-2 genome may enable it to hide in plain sight, reducing activation of host pattern recognition receptors (Bowie and Unterholzner 2008). In other well-structured positive-stranded RNA viruses like HCV and MNV, the formation of genome-scale ordered RNA structure (GORS) correlates with decreased activation of antiviral pathways (McFadden et al 2013;Tuplin 2015). Cell-based assays have shown that highly structured viral transcripts have a reduced propensity to activate interferon responses when compared with less structured viral RNAs (Witteveldt et al 2014).…”

Section: Discussionmentioning

confidence: 99%

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

Tavares

Mahadeshwar

Pyle

2020

Preprint

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AbstractSARS-CoV-2 is the causative viral agent of COVID-19, the disease at the center of the current global pandemic. While knowledge of highly structured regions is integral for mechanistic insights into the viral infection cycle, very little is known about the location and folding stability of functional elements within the massive, ~30kb SARS-CoV-2 RNA genome. In this study, we analyze the folding stability of this RNA genome relative to the structural landscape of other well-known viral RNAs. We present an in-silico pipeline to locate regions of high base pair content across this long genome and also identify well-defined RNA structures, a method that allows for direct comparisons of RNA structural complexity within the several domains in SARS-CoV-2 genome. We report that the SARS-CoV-2 genomic propensity to stable RNA folding is exceptional among RNA viruses, superseding even that of HCV, one of the most highly structured viral RNAs in nature. Furthermore, our analysis reveals varying levels of RNA structure across genomic functional regions, with accessory and structural ORFs containing the highest structural density in the viral genome. Finally, we take a step further to examine how individual RNA structures formed by these ORFs are affected by the differences in genomic and subgenomic contexts. The conclusions reported in this study provide a foundation for structure-function hypotheses in SARS-CoV-2 biology, and in turn, may guide the 3D structural characterization of potential RNA drug targets for COVID-19 therapeutics.

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“…RNA secondary structures perform a wide range of important biological functions in addition to their central roles in ribosomes and tRNAs. Auxiliary structural functions include regulating gene expression levels in mammalian cells (2), constraining mutations during bacterial evolution (7), controlling temperature sensitivity (3, 12, 36) and viral replication (1, 34, 35), regulating folding and post-translational modification of encoded proteins (14, 15).…”

Section: Introductionmentioning

confidence: 99%

Computational Discovery of Evolutionary Conserved Enterovirus 71 RNA Secondary Structures

Fridlyand

Lukashev

Chursov³

et al. 2018

Preprint

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Viral RNAs store information in their sequence and structure. Little, however is known about the contribution of RNA structure to viral replication and evolution. We previously described RNA ISRAEU to computationally identify structured regions in viral RNA based on evolutionary conservation of predicted structures. Here, we apply RNA GUESS (Generator of Uniformly Evolved Secondary Structures) to better understand enterovirus 71, a highly pathogenic human picornavirus. RNA GUESS identified previously known evolutionarily conserved picornavirus RNA structures, and uniquely predicted RNA structures with significant structural conservation despite the lack of an obvious sequence conservation. One structure consists of a stretch of obligatorily unpaired nucleotides that can potentially interact with RNA-binding proteins and siRNAs. Another, forms a potential RNA switch that can form two alternative structures while the third and fourth constitute hairpin-like structures. These findings provide a launching point for physical and genetic studies regarding the function and structures of these RNA elements.

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Diverse roles and interactions of RNA structures during the replication of positive-stranded RNA viruses of humans and animals

Cited by 19 publications

References 46 publications

Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly

Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly

The global and local distribution of RNA structure throughout the SARS-CoV-2 genome

Computational Discovery of Evolutionary Conserved Enterovirus 71 RNA Secondary Structures

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