scholarly journals Molecular Insights into the Flavivirus Replication Complex

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 956
Author(s):  
Kaïn van den Elsen ◽  
Jun Ping Quek ◽  
Dahai Luo
Keyword(s):  
Unmet Need ◽  
Genome Replication ◽  
Replication Process ◽  
Particle Assembly ◽  
Virus Family ◽  
Replication Complex ◽  
Molecular Events ◽  
Virus Rna ◽  
Viral Genome Replication ◽  
Molecular Aspects

Flaviviruses are vector-borne RNA viruses, many of which are clinically relevant human viral pathogens, such as dengue, Zika, Japanese encephalitis, West Nile and yellow fever viruses. Millions of people are infected with these viruses around the world each year. Vaccines are only available for some members of this large virus family, and there are no effective antiviral drugs to treat flavivirus infections. The unmet need for vaccines and therapies against these flaviviral infections drives research towards a better understanding of the epidemiology, biology and immunology of flaviviruses. In this review, we discuss the basic biology of the flavivirus replication process and focus on the molecular aspects of viral genome replication. Within the virus-induced intracellular membranous compartments, flaviviral RNA genome replication takes place, starting from viral poly protein expression and processing to the assembly of the virus RNA replication complex, followed by the delivery of the progeny viral RNA to the viral particle assembly sites. We attempt to update the latest understanding of the key molecular events during this process and highlight knowledge gaps for future studies.

scholarly journals Dimerisation of the influenza virus RNA polymerase during viral genome replication

2019 ◽  
Vol 1 (1A) ◽  
Author(s):  
Alexander Walker ◽  
Haitian Fan ◽  
Loic Carrique ◽  
Jeremy Keown ◽  
David Bauer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Rna Polymerase ◽  
Viral Genome ◽  
Genome Replication ◽  
Virus Rna ◽  
Viral Genome Replication

scholarly journals Mosquito metabolomics reveal that dengue virus replication requires phospholipid reconfiguration via the remodeling cycle

2020 ◽  
Vol 117 (44) ◽  
pp. 27627-27636
Author(s):  
Thomas Vial ◽  
Wei-Lian Tan ◽  
Eric Deharo ◽  
Dorothée Missé ◽  
Guillaume Marti ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Viral Genome ◽  
De Novo ◽  
Genome Replication ◽  
Mosquito Vector ◽  
Phospholipid Biosynthesis ◽  
Replication Complex ◽  
Mosquito Cells ◽  
Viral Genome Replication ◽  
Blood Meals

Dengue virus (DENV) subdues cell membranes for its cellular cycle by reconfiguring phospholipids in humans and mosquitoes. Here, we determined how and why DENV reconfigures phospholipids in the mosquito vector. By inhibiting and activating the de novo phospholipid biosynthesis, we demonstrated the antiviral impact of de novo–produced phospholipids. In line with the virus hijacking lipids for its benefit, metabolomics analyses indicated that DENV actively inhibited the de novo phospholipid pathway and instead triggered phospholipid remodeling. We demonstrated the early induction of remodeling during infection by using isotope tracing in mosquito cells. We then confirmed in mosquitoes the antiviral impact of de novo phospholipids by supplementing infectious blood meals with a de novo phospholipid precursor. Eventually, we determined that phospholipid reconfiguration was required for viral genome replication but not for the other steps of the virus cellular cycle. Overall, we now propose that DENV reconfigures phospholipids through the remodeling cycle to modify the endomembrane and facilitate formation of the replication complex. Furthermore, our study identified de novo phospholipid precursor as a blood determinant of DENV human-to-mosquito transmission.

scholarly journals Function, Architecture, and Biogenesis of Reovirus Replication Neoorganelles

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 288 ◽  
Author(s):  
Raquel Tenorio ◽  
Isabel Fernández de Castro ◽  
Jonathan J. Knowlton ◽  
Paula F. Zamora ◽  
Danica M. Sutherland ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Host Cells ◽  
Genome Replication ◽  
Nonstructural Proteins ◽  
Particle Assembly ◽  
The Matrix ◽  
Viral Genome Replication ◽  
Pathogenic Viruses ◽  
Infected Cells ◽  
Reovirus Replication

Most viruses that replicate in the cytoplasm of host cells form neoorganelles that serve as sites of viral genome replication and particle assembly. These highly specialized structures concentrate viral proteins and nucleic acids, prevent the activation of cell-intrinsic defenses, and coordinate the release of progeny particles. Reoviruses are common pathogens of mammals that have been linked to celiac disease and show promise for oncolytic applications. These viruses form nonenveloped, double-shelled virions that contain ten segments of double-stranded RNA. Replication organelles in reovirus-infected cells are nucleated by viral nonstructural proteins µNS and σNS. Both proteins partition the endoplasmic reticulum to form the matrix of these structures. The resultant membranous webs likely serve to anchor viral RNA–protein complexes for the replication of the reovirus genome and the assembly of progeny virions. Ongoing studies of reovirus replication organelles will advance our knowledge about the strategies used by viruses to commandeer host biosynthetic pathways and may expose new targets for therapeutic intervention against diverse families of pathogenic viruses.

scholarly journals Reovirus σNS and μNS Proteins Remodel the Endoplasmic Reticulum to Build Replication Neo-Organelles

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Raquel Tenorio ◽  
Isabel Fernández de Castro ◽  
Jonathan J. Knowlton ◽  
Paula F. Zamora ◽  
Christopher H. Lee ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Viral Infection ◽  
Viral Genome ◽  
Electron Tomography ◽  
Light And Electron Microscopy ◽  
Genome Replication ◽  
Particle Assembly ◽  
Viral Genome Replication ◽  
Reovirus Replication ◽  
Cellular Compartments

ABSTRACTLike most viruses that replicate in the cytoplasm, mammalian reoviruses assemble membranous neo-organelles called inclusions that serve as sites of viral genome replication and particle morphogenesis. Viral inclusion formation is essential for viral infection, but how these organelles form is not well understood. We investigated the biogenesis of reovirus inclusions. Correlative light and electron microscopy showed that endoplasmic reticulum (ER) membranes are in contact with nascent inclusions, which form by collections of membranous tubules and vesicles as revealed by electron tomography. ER markers and newly synthesized viral RNA are detected in inclusion internal membranes. Live-cell imaging showed that early in infection, the ER is transformed into thin cisternae that fragment into small tubules and vesicles. We discovered that ER tubulation and vesiculation are mediated by the reovirus σNS and μNS proteins, respectively. Our results enhance an understanding of how viruses remodel cellular compartments to build functional replication organelles.IMPORTANCEViruses modify cellular structures to build replication organelles. These organelles serve as sites of viral genome replication and particle morphogenesis and are essential for viral infection. However, how these organelles are constructed is not well understood. We found that the replication organelles of mammalian reoviruses are formed by collections of membranous tubules and vesicles derived from extensive remodeling of the peripheral endoplasmic reticulum (ER). We also observed that ER tubulation and vesiculation are triggered by the reovirus σNS and μNS proteins, respectively. Our results enhance an understanding of how viruses remodel cellular compartments to build functional replication organelles and provide functions for two enigmatic reovirus replication proteins. Most importantly, this research uncovers a new mechanism by which viruses form factories for particle assembly.

scholarly journals Structural and phenotypic analysis of Chikungunya Virus RNA structures during viral genome replication and translation

2019 ◽  
Vol 1 (1A) ◽  
Author(s):  
Catherine Kendall ◽  
Henna Khalid ◽  
Marietta Mueller ◽  
Alain Kohl ◽  
Andres Merits ◽  
...  
Keyword(s):  
Viral Genome ◽  
Chikungunya Virus ◽  
Genome Replication ◽  
Rna Structures ◽  
Phenotypic Analysis ◽  
Virus Rna ◽  
Viral Genome Replication

scholarly journals Structures of influenza A virus RNA polymerase offer insight into viral genome replication

Nature ◽  
2019 ◽  
Vol 573 (7773) ◽  
pp. 287-290 ◽  
Author(s):  
Haitian Fan ◽  
Alexander P. Walker ◽  
Loïc Carrique ◽  
Jeremy R. Keown ◽  
Itziar Serna Martin ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Influenza A Virus ◽  
Viral Genome ◽  
Influenza A ◽  
Genome Replication ◽  
Virus Rna ◽  
Viral Genome Replication ◽  
Insight Into

RNA-dependent structures of the RNA-binding loop in the flavivirus NS3 helicase

2020 ◽  
Author(s):  
Russell B. Davidson ◽  
Josie Hendrix ◽  
Brian J. Geiss ◽  
Martin McCullagh
Keyword(s):  
Rna Binding ◽  
Umbrella Sampling ◽  
Nucleoside Triphosphate ◽  
Genome Replication ◽  
Free Energy Surface ◽  
Structural Element ◽  
Replication Process ◽  
Ns3 Protein ◽  
Viral Genome Replication ◽  
Binding Loop

AbstractThe flavivirus NS3 protein is a helicase that has pivotal functions during the viral genome replication process, where it unwinds double-stranded RNA and translocates along the nucleic acid polymer in a nucleoside triphosphate hydrolysis-dependent mechanism. An increased interest in this enzyme as a potential target for development of antiviral therapeutics was sparked by the 2015 Zika virus epidemic in the Americas. Crystallographic and computational studies of the flavivirus NS3 helicase have identified the RNA-binding loop as an interesting structural element, which may function as an origin for the RNA-enhanced NTPase activity observed for this family of helicases. Microsecond-long unbiased molecular dynamics as well as extensive replica exchange umbrella sampling simulations of the Zika NS3 helicase have been performed to investigate the RNA-dependence of this loop’s structural conformations. Specifically, the effect of the bound single-stranded RNA (ssRNA) oligomer on the putative “open” and “closed” conformations of this loop are studied. In the Apo substrate state, the two structures are nearly isoergonic (ΔGO→C = −0.22 kcal mol−1), explaining the structural ambiguity observed in Apo NS3h crystal structures. The bound ssRNA is seen to stabilize the “open” conformation (ΔGO→C = 1.97 kcal mol−1) through direct protein-RNA interactions at the top of the loop. Interestingly, a small ssRNA oligomer bound over 13 Å away from the loop is seen to affect the free energy surface to favor the “open” structure while minimizing barriers between the two states. The mechanism of the transition between “open” and “closed” states is characterized as are residues of importance for the RNA-binding loop structures. From these results, the loop is hypothesized to be a viable region in the protein for targeted small-molecule inhibition and mutagenesis studies, where stabilization of the “closed” RNA-binding loop will negatively impact RNA-binding and the RNA-enhanced NTPase activity.

Coronavirus: history, genome structure and pathogenesis

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Poonam B ◽  
Prabhjot Kaur Gill
Keyword(s):  
Genome Structure ◽  
Public Health Research ◽  
Replication Process ◽  
Virus Family ◽  
Enveloped Virus ◽  
Target Organs ◽  
Transcription Process ◽  
Recent Emergence ◽  
The Family ◽  
Discontinuous Transcription

Background: The positive sense and inordinate large RNA genome are enclosed by helical nuceocapsids along with an outermost layer belongs to the family Coronaviridae. The phylogenetic tree of this family has been quartered into Class1 as alpha, Class 2 as beta, Class 3 as gamma and Class 4 as delta CoV. The mammalian respiratory and gastrointestinal tracts are the main target organs of this enveloped virus with misperceived mechanisms. The relevance of this virus family has considerably increased by the dint of recent emergence of the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), which are caused by viruses belonging to the beta-CoV group. Aim: Aforesaid illustrations of emergence of coronavirus diseases over the past two decades, SARS (2002 and 2003) and MERS (2012 to present) - the ongoing COVID-19 outbreak has pressurized the WHO to take innovative measures for public health, research and medical communities. The aim of the present review is to have proficiency in coronavirus replication and transcription process which is still in its infancy. Conclusion: An outcome of epidemics, it is being recognized as one of the most advancing viruses by the virtue of high genomic nucleotide substitution rates and recombination. The hallmark of coronavirus replication is discontinuous transcription resulting in the production of multiple subgenomic mRNAs having sequences complementary to both ends of the genome. Therefore, complete genome sequence of coronavirus will be used as frame of reference for knowing this classical phenomenon of RNA replication process. Finally, research on the pathogenesis of coronaviruses and the host immunopathological response will aid in designing vaccines and minimizing mortality rate.

scholarly journals Genome-Wide Analyses Reveal Genetic Convergence of Prolificacy between Goats and Sheep

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 480
Author(s):  
Lin Tao ◽  
Xiaoyun He ◽  
Yanting Jiang ◽  
Yufang Liu ◽  
Yina Ouyang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Litter Size ◽  
Luteal Phase ◽  
Antigen Processing ◽  
Osteoclast Differentiation ◽  
Follicular Phase ◽  
Comparative Genomic ◽  
Genome Replication ◽  
Viral Genome Replication ◽  
Transcriptomic Level

The litter size of domestic goats and sheep is an economically important trait that shows variation within breeds. Strenuous efforts have been made to understand the genetic mechanisms underlying prolificacy in goats and sheep. However, there has been a paucity of research on the genetic convergence of prolificacy between goats and sheep, which likely arose because of similar natural and artificial selection forces. Here, we performed comparative genomic and transcriptomic analyses to identify the genetic convergence of prolificacy between goats and sheep. By combining genomic and transcriptomic data for the first time, we identified this genetic convergence in (1) positively selected genes (CHST11 and SDCCAG8), (2) differentially expressed genes (SERPINA14, RSAD2, and PPIG at follicular phase, and IGF1, GPRIN3, LIPG, SLC7A11, and CHST15 at luteal phase), and (3) biological pathways (genomic level: osteoclast differentiation, ErbB signaling pathway, and relaxin signaling pathway; transcriptomic level: the regulation of viral genome replication at follicular phase, and protein kinase B signaling and antigen processing and presentation at luteal phase). These results indicated the potential physiological convergence and enhanced our understanding of the overlapping genetic makeup underlying litter size in goats and sheep.

Alternative translation and alternative RNA processing mechanism in parvovirus RNA processing

2014 ◽  
Author(s):  
◽  
Olufemi Fasina
Keyword(s):  
Gene Expression ◽  
Rna Processing ◽  
Viral Genome ◽  
Transcription Initiation ◽  
Alternative Polyadenylation ◽  
Open Reading Frames ◽  
Genome Replication ◽  
University Of Missouri ◽  
Diverse Range ◽  
Viral Genome Replication

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Viruses as obligate intracellular metabolic parasite require the capacity to orchestrate and modulate the host environment either in the nucleus or cytoplasm for their efficient reproductive life cycle. This warrants the use of diverse range of proteins expressed from the viral genome with the ability of regulating viral genome replication, transcription and translation, in addition antagonizing host factors inhibitory to the virus. Therefore, in order to achieve these goals, viruses utilizes gene expression strategies to expand their coding capacity. Gene expression mechanism such as transcription initiation, capping, splicing and 3�-end processing afford viruses the opportunities to utilize the eukaryotic metabolic machineries for generating proteome diversity. Parvoviruses and other DNA viruses effectively capitalize on their use of nuclear eukaryotic metabolic machineries to co-opt host cell factors for optimal replication and gene expression. Parvoviruses with small genome size and overlapping open reading frames utilize alternative transcription initiation, alternative splicing and alternative polyadenylation to co-ordinate the expression of its non-structural and structural proteins. In this work, we have characterized how two parvoviruses; Dependovirus AAV5 and Bocavirus Minute virus of canine (MVC) utilize alternative gene expression mechanisms and strategies to optimize expression of viral proteins from their genome.

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