scholarly journals Homologous recombination is an intrinsic defense against antiviral RNA interference

2018 ◽  
Vol 115 (39) ◽  
pp. E9211-E9219 ◽  
Author(s):  
Lauren C. Aguado ◽  
Tristan X. Jordan ◽  
Emily Hsieh ◽  
Daniel Blanco-Melo ◽  
John Heard ◽  
...  
Keyword(s):  
Rna Interference ◽  
Homologous Recombination ◽  
Virus Replication ◽  
Defense Mechanism ◽  
Selective Pressure ◽  
Rna Viruses ◽  
Antiviral Defense ◽  
Dynamic Relationship ◽  
Pathogen Prevalence ◽  
Genomic Material

RNA interference (RNAi) is the major antiviral defense mechanism of plants and invertebrates, rendering the capacity to evade it a defining factor in shaping the viral landscape. Here we sought to determine whether different virus replication strategies provided any inherent capacity to evade RNAi in the absence of an antagonist. Through the exploitation of host microRNAs, we recreated an RNAi-like environment in vertebrates and directly compared the capacity of positive- and negative-stranded RNA viruses to cope with this selective pressure. Applying this defense against four distinct viral families revealed that the capacity to undergo homologous recombination was the defining attribute that enabled evasion of this defense. Independent of gene expression strategy, positive-stranded RNA viruses that could undergo strand switching rapidly excised genomic material, while negative-stranded viruses were effectively targeted and cleared upon RNAi-based selection. These data suggest a dynamic relationship between host antiviral defenses and the biology of virus replication in shaping pathogen prevalence.

scholarly journals Antiviral Defense Involves AGO4 in an Arabidopsis–Potexvirus Interaction

2016 ◽  
Vol 29 (11) ◽  
pp. 878-888 ◽  
Author(s):  
Chantal Brosseau ◽  
Mohamed El Oirdi ◽  
Ayooluwa Adurogbangba ◽  
Xiaofang Ma ◽  
Peter Moffett
Keyword(s):  
Gene Expression ◽  
Nuclear Localization ◽  
Rna Silencing ◽  
Defense Mechanism ◽  
Rna Viruses ◽  
Antiviral Defense ◽  
Double Stranded Rna ◽  
Micro Rnas ◽  
Plantago Asiatica ◽  
Antiviral Activities

In plants, RNA silencing regulates gene expression through the action of Dicer-like (DCL) and Argonaute (AGO) proteins via micro RNAs and RNA-dependent DNA methylation (RdDM). In addition, RNA silencing functions as an antiviral defense mechanism by targeting virus-derived double-stranded RNA. Plants encode multiple AGO proteins with specialized functions, including AGO4-like proteins that affect RdDM and AGO2, AGO5, and AGO1, which have antiviral activities. Here, we show that AGO4 is also required for defense against the potexvirus Plantago asiatica mosaic virus (PlAMV), most likely independent of RdDM components such as DCL3, Pol IV, and Pol V. Transient assays showed that AGO4 has direct antiviral activity on PlAMV and, unlike RdDM, this activity does not require nuclear localization of AGO4. Furthermore, although PlAMV infection causes a decrease in AGO4 expression, PlAMV causes a change in AGO4 localization from a largely nuclear to a largely cytoplasmic distribution. These results indicate an important role for AGO4 in targeting plant RNA viruses as well as demonstrating novel mechanisms of regulation of and by AGO4, independent of its canonical role in regulating gene expression by RdDM.

scholarly journals Terminal uridylyltransferases target RNA viruses as part of the innate immune system in animals

2017 ◽  
Author(s):  
Jérémie Le Pen ◽  
Hongbing Jiang ◽  
Tomás Di Domenico ◽  
Emma Kneuss ◽  
Joanna Kosałka ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Large Scale ◽  
Defense Mechanism ◽  
Rna Viruses ◽  
Interferon Response ◽  
Rnai Pathway ◽  
Antiviral Defense ◽  
C Elegans ◽  
Protein Levels

RNA viruses are a major threat to animals and plants. RNA interference (RNAi) and the interferon response provide innate antiviral defense against RNA viruses. Here we performed a large-scale screen using C. elegans and its natural pathogen, the Orsay virus (OrV), and identified cde-1 as important for antiviral defense. CDE-1 is a homologue of the mammalian TUT4/7 terminal uridylyltransferases; its catalytic activity is required for its antiviral function. CDE-1 uridylates the 3′ end of the OrV RNA genome and promotes its degradation, independently of the RNAi pathway. Likewise, TUT4/7 uridylate influenza A virus (IAV) mRNAs in mammalian cells. Deletion of TUT4/7 leads to increased IAV mRNA and protein levels. We have defined 3′ terminal uridylation of viral RNAs as a conserved antiviral defense mechanism.

scholarly journals RNA Helicase A Regulates the Replication of RNA Viruses

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 361
Author(s):  
Rui-Zhu Shi ◽  
Yuan-Qing Pan ◽  
Li Xing
Keyword(s):  
Virus Replication ◽  
Rna Binding ◽  
Rna Viruses ◽  
Rna Helicase ◽  
Rna Helicase A ◽  
Double Stranded Rna ◽  
Binding Domains ◽  
N Terminus

The RNA helicase A (RHA) is a member of DExH-box helicases and characterized by two double-stranded RNA binding domains at the N-terminus. RHA unwinds double-stranded RNA in vitro and is involved in RNA metabolisms in the cell. RHA is also hijacked by a variety of RNA viruses to facilitate virus replication. Herein, this review will provide an overview of the role of RHA in the replication of RNA viruses.

scholarly journals Regulation of the protein kinase PKR by the vaccinia virus pseudosubstrate inhibitor K3L is dependent on residues conserved between the K3L protein and the PKR substrate eIF2alpha.

1997 ◽  
Vol 17 (7) ◽  
pp. 4146-4158 ◽  
Author(s):  
M Kawagishi-Kobayashi ◽  
J B Silverman ◽  
T L Ung ◽  
T E Dever
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Vaccinia Virus ◽  
Defense Mechanism ◽  
Mutational Analysis ◽  
Substrate Recognition ◽  
Phosphorylation Site ◽  
Antiviral Defense ◽  
Loss Of Function ◽  
Yeast Saccharomyces Cerevisiae

The mammalian double-stranded RNA-activated protein kinase PKR is a component of the cellular antiviral defense mechanism and phosphorylates Ser-51 on the alpha subunit of the translation factor eIF2 to inhibit protein synthesis. To identify the molecular determinants that specify substrate recognition by PKR, we performed a mutational analysis on the vaccinia virus K3L protein, a pseudosubstrate inhibitor of PKR. High-level expression of PKR is lethal in the yeast Saccharomyces cerevisiae because PKR phosphorylates eIF2alpha and inhibits protein synthesis. We show that coexpression of vaccinia virus K3L can suppress the growth-inhibitory effects of PKR in yeast, and using this system, we identified both loss-of-function and hyperactivating mutations in K3L. Truncation of, or point mutations within, the C-terminal portion of the K3L protein, homologous to residues 79 to 83 in eIF2alpha, abolished PKR inhibitory activity, whereas the hyperactivating mutation, K3L-H47R, increased the homology between the K3L protein and eIF2alpha adjacent to the phosphorylation site at Ser-51. Biochemical and yeast two-hybrid analyses revealed that the suppressor phenotype of the K3L mutations correlated with the affinity of the K3L protein for PKR and was inversely related to the level of eIF2alpha phosphorylation in the cell. These results support the idea that residues conserved between the pseudosubstrate K3L protein and the authentic substrate eIF2alpha play an important role in substrate recognition, and they suggest that PKR utilizes sequences both near and over 30 residues from the site of phosphorylation for substrate recognition. Finally, by reconstituting part of the mammalian antiviral defense mechanism in yeast, we have established a genetically useful system to study viral regulators of PKR.

RNA Interference Mechanisms and Applications in Plant Pathology

2018 ◽  
Vol 56 (1) ◽  
pp. 581-610 ◽  
Author(s):  
Cristina Rosa ◽  
Yen-Wen Kuo ◽  
Hada Wuriyanghan ◽  
Bryce W. Falk
Keyword(s):  
Plant Pathology ◽  
Rna Interference ◽  
Gene Function ◽  
Small Rnas ◽  
Plant Pathogens ◽  
Common Ancestor ◽  
Plant Protection ◽  
Plant Diseases ◽  
Antiviral Defense ◽  
Endogenous Genes

The origin of RNA interference (RNAi), the cell sentinel system widely shared among eukaryotes that recognizes RNAs and specifically degrades or prevents their translation in cells, is suggested to predate the last eukaryote common ancestor ( 138 ). Of particular relevance to plant pathology is that in plants, but also in some fungi, insects, and lower eukaryotes, RNAi is a primary and effective antiviral defense, and recent studies have revealed that small RNAs (sRNAs) involved in RNAi play important roles in other plant diseases, including those caused by cellular plant pathogens. Because of this, and because RNAi can be manipulated to interfere with the expression of endogenous genes in an intra- or interspecific manner, RNAi has been used as a tool in studies of gene function but also for plant protection. Here, we review the discovery of RNAi, canonical mechanisms, experimental and translational applications, and new RNA-based technologies of importance to plant pathology.

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