The Experts below are selected from a list of 1443 Experts worldwide ranked by ideXlab platform
Sara L Sawyer - One of the best experts on this subject based on the ideXlab platform.
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XRN1 is a species specific virus restriction factor in yeasts
PLOS Pathogens, 2016Co-Authors: Paul A. Rowley, Brandon Ho, Sarah Bushong, Arlen W Johnson, Sara L SawyerAbstract:In eukaryotes, the degradation of cellular mRNAs is accomplished by XRN1 and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. We find a highly refined, species-specific relationship between XRN1p and the “L-A” totiviruses of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in high levels of XRN1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with the L-A virus, where XRN1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and XRN1p from S. kudriavzevii is most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All XRN1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, XRN1p appears to co-evolve with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. We demonstrate that XRN1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more complicated than just XRN1p-mediated nucleolytic digestion of viral RNAs.
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XRN1 is a Species-Specific Virus Restriction Factor in Yeasts
bioRxiv, 2016Co-Authors: Paul A. Rowley, Brandon Ho, Sarah Bushong, Arlen W Johnson, Sara L SawyerAbstract:In eukaryotes, the degradation of cellular mRNAs is accomplished by XRN1p and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. One model is that yeast viruses are subject to degradation simply as a result of the intrinsic exonuclease activity of proteins involved in RNA metabolism. Contrary to this model, we find a highly refined, species-specific relationship between XRN1p and the double-stranded L-A totivirus of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in XRN1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with yeast viruses, where XRN1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and XRN1p from S. kudriavzevii being most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All XRN1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, the activity of XRN1p against totiviruses is not an incidental consequence of the enzymatic activity of XRN1p, but rather XRN1p co-evolves with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. Consistent with this, we demonstrated that XRN1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more involved that XRN1p-mediated nucleolytic digestion of viral RNAs.
Arlen W Johnson - One of the best experts on this subject based on the ideXlab platform.
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XRN1 is a species specific virus restriction factor in yeasts
PLOS Pathogens, 2016Co-Authors: Paul A. Rowley, Brandon Ho, Sarah Bushong, Arlen W Johnson, Sara L SawyerAbstract:In eukaryotes, the degradation of cellular mRNAs is accomplished by XRN1 and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. We find a highly refined, species-specific relationship between XRN1p and the “L-A” totiviruses of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in high levels of XRN1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with the L-A virus, where XRN1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and XRN1p from S. kudriavzevii is most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All XRN1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, XRN1p appears to co-evolve with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. We demonstrate that XRN1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more complicated than just XRN1p-mediated nucleolytic digestion of viral RNAs.
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XRN1 is a Species-Specific Virus Restriction Factor in Yeasts
bioRxiv, 2016Co-Authors: Paul A. Rowley, Brandon Ho, Sarah Bushong, Arlen W Johnson, Sara L SawyerAbstract:In eukaryotes, the degradation of cellular mRNAs is accomplished by XRN1p and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. One model is that yeast viruses are subject to degradation simply as a result of the intrinsic exonuclease activity of proteins involved in RNA metabolism. Contrary to this model, we find a highly refined, species-specific relationship between XRN1p and the double-stranded L-A totivirus of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in XRN1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with yeast viruses, where XRN1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and XRN1p from S. kudriavzevii being most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All XRN1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, the activity of XRN1p against totiviruses is not an incidental consequence of the enzymatic activity of XRN1p, but rather XRN1p co-evolves with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. Consistent with this, we demonstrated that XRN1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more involved that XRN1p-mediated nucleolytic digestion of viral RNAs.
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inhibition of mrna turnover in yeast by an XRN1 mutation enhances the requirement for eif4e binding to eif4g and for proper capping of transcripts by ceg1p
Genetics, 2000Co-Authors: Justin T Brown, Xianmei Yang, Arlen W JohnsonAbstract:Null mutants of XRN1, encoding the major cytoplasmic exoribonuclease in yeast, are viable but accumulate decapped, deadenylated transcripts. A screen for mutations synthetic lethal with XRN1Delta identified a mutation in CDC33, encoding eIF4E. This mutation (glutamate to glycine at position 72) affected a highly conserved residue involved in interaction with eIF4G. Synthetic lethality between XRN1 and cdc33 was not relieved by high-copy expression of eIF4G or by disruption of the yeast eIF4E binding protein Caf20p. High-copy expression of a mutant eIF4G defective for eIF4E binding resulted in a dominant negative phenotype in an XRN1 mutant, indicating the importance of this interaction in an XRN1 mutant. Another allele of CDC33, cdc33-1, along with mutations in CEG1, encoding the nuclear guanylyltransferase, were also synthetic lethal with XRN1Delta, whereas mutations in PRT1, encoding a subunit of eIF3, were not. Mutations in CDC33, CEG1, PRT1, PAB1, and TIF4631, encoding eIF4G1, have been shown to lead to destabilization of mRNAs. Although such destabilization in cdc33, ceg1, and pab1 mutants can be partially suppressed by an XRN1 mutation, we observed synthetic lethality between XRN1 and either cdc33 or ceg1 and no suppression of the inviability of a pab1 null mutation by XRN1Delta. Thus, the inhibition of mRNA turnover by blocking XRN1p function does not suppress the lethality of defects upstream in the turnover pathway but it does enhance the requirement for (7)mG caps and for proper formation of the eIF4E/eIF4G cap recognition complex.
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rat1p and XRN1p are functionally interchangeable exoribonucleases that are restricted to and required in the nucleus and cytoplasm respectively
Molecular and Cellular Biology, 1997Co-Authors: Arlen W JohnsonAbstract:XRN1 encodes an abundant cytoplasmic exoribonuclease, XRN1p, responsible for mRNA turnover in yeast. A screen for bypass suppressors of the inviability of XRN1 ski2 double mutants identified dominant alleles of RAT1, encoding an exoribonuclease homologous with XRN1p. These RAT1 alleles restored XRN1-like functions, including cytoplasmic RNA turnover, wild-type sensitivity to the microtubule-destabilizing drug benomyl, and sporulation. The mutations were localized to a region of the RAT1 gene encoding a putative bipartite nuclear localization sequence (NLS). Fusions to green fluorescent protein were used to demonstrate that wild-type Rat1p is localized to the nucleus and that the mutant alleles result in mislocalization of Rat1p to the cytoplasm. Conversely, targeting XRN1p to the nucleus by the addition of the simian virus 40 large-T-antigen NLS resulted in complementation of the temperature sensitivity of a rat1-1 strain. These results indicate that XRN1p and Rat1p are functionally interchangeable exoribonucleases that function in and are restricted to the cytoplasm and nucleus, respectively. It is likely that the higher eukaryotic homologs of these proteins will function similarly in the cytoplasm and nucleus.
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synthetic lethality of sep1 XRN1 ski2 and sep1 XRN1 ski3 mutants of saccharomyces cerevisiae is independent of killer virus and suggests a general role for these genes in translation control
Molecular and Cellular Biology, 1995Co-Authors: Arlen W Johnson, Richard D KolodnerAbstract:Strand exchange protein 1 (Sep1) (also referred to as exoribonuclease I [XRN1]) from Saccharomyces cerevisiae has been implicated in DNA recombination, RNA turnover, karyogamy, and G4 DNA pairing among other disparate cellular processes. Using a genetic approach to study the role of SEP1/XRN1 in mitotic yeast cells, we identified mutations in the genes superkiller 2 (SKI2) and superkiller 3 (SKI3) as synthetically lethal with an sep1 null mutation. The SKI genes are thought to comprise an intracellular antiviral system controlling the expression of killer toxin from double-stranded RNA virus found in many yeast strains. However, the lethality of sep1 ski2 and sep1 ski3 mutants was independent of the L-A and M viruses, suggesting that the SKI genes act in a general cellular process in addition to virus control. We propose that Sep1/XRN1 and Ski2 both act to block translation on transcripts targeted for degradation. Using a temperature-sensitive allele of SEP1/XRN1, we show that double mutants display a synthetic cell cycle arrest in late G1 at Start.
Stanley M Lemon - One of the best experts on this subject based on the ideXlab platform.
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Regulation of hepatitis C virus genome replication by microRNA-122.
Uirusu, 2020Co-Authors: Takahiro Masaki, Stanley M LemonAbstract:: microRNA-122 (miR-122) is an abundant, liver-specific miRNA that regulates gene expression post-transcriptionally, typically by binding to the 3' untranslated region (UTR) of mRNAs, repressing their translation and mediating their degradation. Hepatitis C virus (HCV) is uniquely dependent on miR-122. Similar to conventional miRNA action, miR-122 recruits Argonaute-2 (AGO2) protein to the 5' UTR of the viral genome. However, in contrast to typical miRNA function, this stabilizes HCV RNA and slows its decay in infected cells. We found that HCV RNA is degraded primarily by the cytoplasmic 5' exonuclease XRN1 and that miR-122 acts to protect the viral RNA from XRN1-mediated 5' exonucleolytic decay. However, HCV replication still requires miR-122 in XRN1-depleted cells, suggesting additional functions. We also showed that miR-122 enhances HCV RNA synthesis by reducing viral genomes engaged in translation while increasing the fraction available for RNA synthesis. In this review, we summarize the recent progress on the regulatory mechanisms of HCV genome replication by miR-122.
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dissecting the roles of the 5 exoribonucleases XRN1 and xrn2 in restricting hepatitis c virus replication
Journal of Virology, 2015Co-Authors: You Li, Daisuke Yamane, Stanley M LemonAbstract:The replication of hepatitis C virus (HCV) is uniquely dependent on a host microRNA, miR-122. Previous studies using genotype 1a H77S.3 virus demonstrated that miR-122 acts in part by protecting the RNA genome from 5′ decay mediated by the cytoplasmic 5′ exoribonuclease, XRN1. However, this finding has been challenged by a recent report suggesting that a predominantly nuclear exoribonuclease, Xrn2, mediates the degradation of genotype 2a JFH1 RNA. Here, we dissect the roles of these two 5′ exoribonucleases in restricting the replication of different HCV strains and mediating the decay of HCV RNA. Small interfering RNA (siRNA) depletion experiments indicated that XRN1 restricts replication of all HCV strains tested: JFH1, H77S.3, H77D (a robustly replicating genotype 1a variant), and HJ3-5 (a genotype 1a/2a chimeric virus). In contrast, the antiviral effects of Xrn2 were limited to JFH1 and H77D viruses. Moreover, such effects were not apparent in cells infected with a JFH1 luciferase reporter virus. Whereas XRN1 depletion significantly slowed decay of JFH1 and HJ3-5 RNAs, Xrn2 depletion marginally enhanced the JFH1 RNA half-life and had no effect on HJ3-5 RNA decay. The positive effects of XRN1 depletion on JFH1 replication were largely redundant and nonadditive with those of exogenous miR-122 supplementation, whereas Xrn2 depletion acted additively and thus independently of miR-122. We conclude that XRN1 is the dominant 5′ exoribonuclease mediating decay of HCV RNA and that miR-122 provides protection against it. The restriction of JFH1 and H77D replication by Xrn2 is likely indirect in nature and possibly linked to cytopathic effects of these robustly replicating viruses. IMPORTANCE HCV is a common cause of liver disease both within and outside the United States. Its replication is dependent upon a small, liver-specific noncoding RNA, miR-122. Although this requirement has been exploited for the development of an anti-miR-122 antagomir as a host-targeting antiviral, the molecular mechanisms underpinning the host factor activity of miR-122 remain incompletely defined. Conflicting reports suggest miR-122 protects the viral RNA against decay mediated by distinct cellular 5′ exoribonucleases, XRN1 and Xrn2. Here, we compare the roles of these two exoribonucleases in HCV-infected cells and confirm that XRN1, not Xrn2, is primarily responsible for decay of RNA in cells infected with multiple virus strains. Our results clarify previously published research and add to the current understanding of the host factor requirement for miR-122.
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Dissecting the Roles of the 5′ Exoribonucleases XRN1 and Xrn2 in Restricting Hepatitis C Virus Replication
Journal of Virology, 2015Co-Authors: You Li, Daisuke Yamane, Stanley M LemonAbstract:The replication of hepatitis C virus (HCV) is uniquely dependent on a host microRNA, miR-122. Previous studies using genotype 1a H77S.3 virus demonstrated that miR-122 acts in part by protecting the RNA genome from 5′ decay mediated by the cytoplasmic 5′ exoribonuclease, XRN1. However, this finding has been challenged by a recent report suggesting that a predominantly nuclear exoribonuclease, Xrn2, mediates the degradation of genotype 2a JFH1 RNA. Here, we dissect the roles of these two 5′ exoribonucleases in restricting the replication of different HCV strains and mediating the decay of HCV RNA. Small interfering RNA (siRNA) depletion experiments indicated that XRN1 restricts replication of all HCV strains tested: JFH1, H77S.3, H77D (a robustly replicating genotype 1a variant), and HJ3-5 (a genotype 1a/2a chimeric virus). In contrast, the antiviral effects of Xrn2 were limited to JFH1 and H77D viruses. Moreover, such effects were not apparent in cells infected with a JFH1 luciferase reporter virus. Whereas XRN1 depletion significantly slowed decay of JFH1 and HJ3-5 RNAs, Xrn2 depletion marginally enhanced the JFH1 RNA half-life and had no effect on HJ3-5 RNA decay. The positive effects of XRN1 depletion on JFH1 replication were largely redundant and nonadditive with those of exogenous miR-122 supplementation, whereas Xrn2 depletion acted additively and thus independently of miR-122. We conclude that XRN1 is the dominant 5′ exoribonuclease mediating decay of HCV RNA and that miR-122 provides protection against it. The restriction of JFH1 and H77D replication by Xrn2 is likely indirect in nature and possibly linked to cytopathic effects of these robustly replicating viruses. IMPORTANCE HCV is a common cause of liver disease both within and outside the United States. Its replication is dependent upon a small, liver-specific noncoding RNA, miR-122. Although this requirement has been exploited for the development of an anti-miR-122 antagomir as a host-targeting antiviral, the molecular mechanisms underpinning the host factor activity of miR-122 remain incompletely defined. Conflicting reports suggest miR-122 protects the viral RNA against decay mediated by distinct cellular 5′ exoribonucleases, XRN1 and Xrn2. Here, we compare the roles of these two exoribonucleases in HCV-infected cells and confirm that XRN1, not Xrn2, is primarily responsible for decay of RNA in cells infected with multiple virus strains. Our results clarify previously published research and add to the current understanding of the host factor requirement for miR-122.
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mir 122 stimulates hepatitis c virus rna synthesis by altering the balance of viral rnas engaged in replication versus translation
Cell Host & Microbe, 2015Co-Authors: Daisuke Yamane, You Li, Takahiro Masaki, David R Mcgivern, Kyle C Arend, Takanobu Kato, Takaji Wakita, Nathaniel J Moorman, Stanley M LemonAbstract:Summary The liver-specific microRNA, miR-122, stabilizes hepatitis C virus (HCV) RNA genomes by recruiting host argonaute 2 (AGO2) to the 5′ end and preventing decay mediated by exonuclease XRN1. However, HCV replication requires miR-122 in XRN1-depleted cells, indicating additional functions. We show that miR-122 enhances HCV RNA levels by altering the fraction of HCV genomes available for RNA synthesis. Exogenous miR-122 increases viral RNA and protein levels in XRN1-depleted cells, with enhanced RNA synthesis occurring before heightened protein synthesis. Inhibiting protein translation with puromycin blocks miR-122-mediated increases in RNA synthesis, but independently enhances RNA synthesis by releasing ribosomes from viral genomes. Additionally, miR-122 reduces the fraction of viral genomes engaged in protein translation. Depleting AGO2 or PCBP2, which binds HCV RNA in competition with miR-122 and promotes translation, eliminates miR-122 stimulation of RNA synthesis. Thus, by displacing PCBP2, miR-122 reduces HCV genomes engaged in translation while increasing the fraction available for RNA synthesis.
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miR-122 and the hepatitis C RNA genome: More than just stability
RNA Biology, 2013Co-Authors: You Li, Takahiro Masaki, Stanley M LemonAbstract:MicroRNA-122 (miR-122) plays a key role in hepatitis C virus (HCV) replication, but understanding exactly how it functions in the viral lifecycle has been elusive. HCV is a positive-strand virus with a messenger-sense RNA genome, to which miR-122 binds in a non-canonical fashion at two sites near the 5′ end. Recent studies show that miR-122 recruits Ago-2 to the genomic RNA, stabilizing it and slowing its decay in infected cells. This led us to investigate decay pathways that mediate degradation of the viral RNA. We found HCV RNA is degraded primarily by the cytoplasmic 5′ exonuclease XRN1 in infected cells. miR-122 lost its stabilizing effect when cells were depleted of XRN1 using an RNAi strategy, providing strong evidence that miR-122 acts to protect the viral RNA from XRN1-mediated 5′ exonucleolytic decay. However, XRN1 depletion did not rescue replication of a viral mutant defective in miR-122 binding, indicating that there is much more to miR-122’s actions than prevention of XRN1 decay. Here, we con...
Paul A. Rowley - One of the best experts on this subject based on the ideXlab platform.
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XRN1 is a species specific virus restriction factor in yeasts
PLOS Pathogens, 2016Co-Authors: Paul A. Rowley, Brandon Ho, Sarah Bushong, Arlen W Johnson, Sara L SawyerAbstract:In eukaryotes, the degradation of cellular mRNAs is accomplished by XRN1 and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. We find a highly refined, species-specific relationship between XRN1p and the “L-A” totiviruses of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in high levels of XRN1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with the L-A virus, where XRN1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and XRN1p from S. kudriavzevii is most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All XRN1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, XRN1p appears to co-evolve with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. We demonstrate that XRN1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more complicated than just XRN1p-mediated nucleolytic digestion of viral RNAs.
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XRN1 is a Species-Specific Virus Restriction Factor in Yeasts
bioRxiv, 2016Co-Authors: Paul A. Rowley, Brandon Ho, Sarah Bushong, Arlen W Johnson, Sara L SawyerAbstract:In eukaryotes, the degradation of cellular mRNAs is accomplished by XRN1p and the cytoplasmic exosome. Because viral RNAs often lack canonical caps or poly-A tails, they can also be vulnerable to degradation by these host exonucleases. Yeast lack sophisticated mechanisms of innate and adaptive immunity, but do use RNA degradation as an antiviral defense mechanism. One model is that yeast viruses are subject to degradation simply as a result of the intrinsic exonuclease activity of proteins involved in RNA metabolism. Contrary to this model, we find a highly refined, species-specific relationship between XRN1p and the double-stranded L-A totivirus of different Saccharomyces yeast species. We show that the gene XRN1 has evolved rapidly under positive natural selection in Saccharomyces yeast, resulting in XRN1p protein sequence divergence from one yeast species to the next. We also show that these sequence differences translate to differential interactions with yeast viruses, where XRN1p from S. cerevisiae is most efficient at controlling the L-A virus that chronically infects S. cerevisiae, and XRN1p from S. kudriavzevii being most efficient at controlling the L-A-like virus that we have discovered within S. kudriavzevii. All XRN1p orthologs are equivalent in their interaction with another virus-like parasite, the Ty1 retrotransposon. Thus, the activity of XRN1p against totiviruses is not an incidental consequence of the enzymatic activity of XRN1p, but rather XRN1p co-evolves with totiviruses to maintain its potent antiviral activity and limit viral propagation in Saccharomyces yeasts. Consistent with this, we demonstrated that XRN1p physically interacts with the Gag protein encoded by the L-A virus, suggesting a host-virus interaction that is more involved that XRN1p-mediated nucleolytic digestion of viral RNAs.
Takashi Fujita - One of the best experts on this subject based on the ideXlab platform.
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Spatio-temporal characterization of the antiviral activity of the XRN1-DCP1/2 aggregation against cytoplasmic RNA viruses to prevent cell death
Cell Death & Differentiation, 2020Co-Authors: Chen Seng Ng, Dacquin M. Kasumba, Takashi FujitaAbstract:Host nucleases are implicated in antiviral response through the processing of pathogen-derived nucleic acids. Among many host RNases, decapping enzymes DCP1 and 2, and 5′→3′ exonuclease XRN1, which are components of the RNA decay machinery, have been extensively studied in prokaryotes, plants, and invertebrates but less so in mammalian systems. As a result, the implication of XRN1 and DCPs in viral replication, in particular, the spatio-temporal dynamics during RNA viral infections remains elusive. Here, we highlight that XRN1 and DCPs play a critical role in limiting several groups of RNA viral infections. This antiviral activity was not obvious in wild-type cells but clearly observed in type I interferon (IFN-I)-deficient cells. Mechanistically, infection with RNA viruses induced the enrichment of XRN1 and DCPs in viral replication complexes (vRCs), hence forming distinct cytoplasmic aggregates. These aggregates served as sites for direct interaction between XRN1, DCP1/2, and viral ribonucleoprotein that contains viral RNA (vRNA). Although these XRN1-DCP1/2-vRC-containing foci resemble antiviral stress granules (SGs) or P-body (PB), they did not colocalize with known SG markers and did not correlate with critical PB functions. Furthermore, the presence of 5′ mono- and 5′ triphosphate structures on vRNA was not required for the formation of XRN1-DCP1/2-vRC-containing foci. On the other hand, single-, double-stranded, and higher-ordered vRNA species play a role but are not deterministic for efficient formation of XRN1-DCP1/2 foci and consequent antiviral activity in a manner proportional to RNA length. These results highlight the mechanism behind the antiviral function of XRN1-DCP1/2 in RNA viral infections independent of IFN-I response, protein kinase R and PB function.
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spatio temporal characterization of the antiviral activity of the XRN1 dcp1 2 aggregation against cytoplasmic rna viruses to prevent cell death
Cell Death & Differentiation, 2020Co-Authors: Chen Seng Ng, Dacquin M. Kasumba, Takashi FujitaAbstract:: Host nucleases are implicated in antiviral response through the processing of pathogen-derived nucleic acids. Among many host RNases, decapping enzymes DCP1 and 2, and 5'→3' exonuclease XRN1, which are components of the RNA decay machinery, have been extensively studied in prokaryotes, plants, and invertebrates but less so in mammalian systems. As a result, the implication of XRN1 and DCPs in viral replication, in particular, the spatio-temporal dynamics during RNA viral infections remains elusive. Here, we highlight that XRN1 and DCPs play a critical role in limiting several groups of RNA viral infections. This antiviral activity was not obvious in wild-type cells but clearly observed in type I interferon (IFN-I)-deficient cells. Mechanistically, infection with RNA viruses induced the enrichment of XRN1 and DCPs in viral replication complexes (vRCs), hence forming distinct cytoplasmic aggregates. These aggregates served as sites for direct interaction between XRN1, DCP1/2, and viral ribonucleoprotein that contains viral RNA (vRNA). Although these XRN1-DCP1/2-vRC-containing foci resemble antiviral stress granules (SGs) or P-body (PB), they did not colocalize with known SG markers and did not correlate with critical PB functions. Furthermore, the presence of 5' mono- and 5' triphosphate structures on vRNA was not required for the formation of XRN1-DCP1/2-vRC-containing foci. On the other hand, single-, double-stranded, and higher-ordered vRNA species play a role but are not deterministic for efficient formation of XRN1-DCP1/2 foci and consequent antiviral activity in a manner proportional to RNA length. These results highlight the mechanism behind the antiviral function of XRN1-DCP1/2 in RNA viral infections independent of IFN-I response, protein kinase R and PB function.
