A herpesvirus protein selectively inhibits cellular mRNA nuclear export
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE82241 | GEO | 2016/10/18
SECONDARY ACCESSION(S): PRJNA324418
REPOSITORIES: GEO
Similar Datasets
Project description:Heldt2012 - Influenza Virus Replication
The model describes the life cycle of influenza A virus in a mammalian cell including the following steps: attachment of parental virions to the cell membrane, receptor-mediated endocytosis, fusion of the virus envelope with the endosomal membrane, nuclear import of vRNPs, viral transcription and replication, translation of the structural viral proteins, nuclear export of progeny vRNPs and budding of new virions. It also explicitly accounts for the stabilization of cRNA by viral polymerases and NP and the inhibition of vRNP activity by M1 protein binding. In short, the model focuses on the molecular mechanism that controls viral transcription and replication.
This model is described in the article:
Modeling the intracellular dynamics of influenza virus replication to understand the control of viral RNA synthesis.
Heldt FS, Frensing T, Reichl U.
J Virol.
Abstract:
Influenza viruses transcribe and replicate their negative-sense RNA genome inside the nucleus of host cells via three viral RNA species. In the course of an infection, these RNAs show distinct dynamics, suggesting that differential regulation takes place. To investigate this regulation in a systematic way, we developed a mathematical model of influenza virus infection at the level of a single mammalian cell. It accounts for key steps of the viral life cycle, from virus entry to progeny virion release, while focusing in particular on the molecular mechanisms that control viral transcription and replication. We therefore explicitly consider the nuclear export of viral genome copies (vRNPs) and a recent hypothesis proposing that replicative intermediates (cRNA) are stabilized by the viral polymerase complex and the nucleoprotein (NP). Together, both mechanisms allow the model to capture a variety of published data sets at an unprecedented level of detail. Our findings provide theoretical support for an early regulation of replication by cRNA stabilization. However, they also suggest that the matrix protein 1 (M1) controls viral RNA levels in the late phase of infection as part of its role during the nuclear export of viral genome copies. Moreover, simulations show an accumulation of viral proteins and RNA toward the end of infection, indicating that transport processes or budding limits virion release. Thus, our mathematical model provides an ideal platform for a systematic and quantitative evaluation of influenza virus replication and its complex regulation.
With the current parameter set, the model reproduces an infection at a multiplicity of infection (MOI) of 10. Figure 2A of the paper is reproduced here, with parameters kDegRnp and kSynP changed to zeros.
Initial conditions and parameter changes that were used to obtain specific figures in the article can be found in Table A2.
The model has the correct value for kAttLo as 4.55e-04. The value of this parameter mentioned as 4.55e-02 in Table 1 of the paper is incorrect. This is checked with the author.
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2013-08-07 | BIOMD0000000463 | BioModels
Project description:Analysis of cellular response to DHODH inhibition at gene expression level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. Total RNA obtained from HBEC cells subjected to compound 1/compound 1-14 treatment compared to DMSO treatment.
2012-01-17 | E-GEOD-35116 | biostudies-arrayexpress
Project description:Analysis of cellular response to DHODH inhibition at gene expression level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. Total RNA obtained from HBEC cells subjected to 3 hours compound 1 treatment compared to DMSO treatment.
2012-01-17 | E-GEOD-35115 | biostudies-arrayexpress
Project description:Analysis of cellular response to DHODH inhibition at gene expression and nuclear/cytoplasmic distribution level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. Five million 293T cells were non-transfected or transfected with 6ug of pEGFPN3-M-GFP for 16h. Then, cells were untreated or treated with compound 1(5uM) for 24h. RNA from total cell extracts or from nuclear or cytoplasmic fractions were obtained
2012-01-17 | E-GEOD-35112 | biostudies-arrayexpress
Project description:Analysis of cellular response to DHODH inhibition at gene expression and nuclear/cytoplasmic distribution level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. Five million 293T cells were non-transfected or transfected with 6ug of pCAGGS-NS1 for 16h. Then, cells were untreated or treated with compound 1(5uM) for 24h. RNA from total cell extracts or from nuclear or cytoplasmic fractions were obtained
2012-01-17 | E-GEOD-35113 | biostudies-arrayexpress
Project description:Analysis of cellular response to DHODH inhibition at gene expression and nuclear/cytoplasmic distribution level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors. Five million 293T cells were non-transfected or transfected with 6ug of pCAGGS-NS1 for 16h. Then, cells were untreated or treated with compound 1(5uM) for 24h. RNA from total cell extracts or from nuclear or cytoplasmic fractions were obtained
2012-01-17 | E-GEOD-35114 | biostudies-arrayexpress
Project description:Analysis of cellular response to DHODH inhibition at gene expression and nuclear/cytoplasmic distribution level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors.
2012-01-17 | GSE35114 | GEO
Project description:Analysis of cellular response to DHODH inhibition at gene expression and nuclear/cytoplasmic distribution level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors.
2012-01-17 | GSE35113 | GEO
Project description:Analysis of cellular response to DHODH inhibition at gene expression and nuclear/cytoplasmic distribution level. The NS1 protein of influenza virus is a major virulence factor essential for virus replication as it re-directs the host cell to promote viral protein expression. NS1 inhibits cellular mRNA processing and export, down-regulating host gene expression and enhancing viral gene expression. We report here the identification of a non-toxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for *de novo* pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of VSV M protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors.
2012-01-17 | GSE35112 | GEO
Project description:Epstein-Barr virus (EBV) Rta is a latent-lytic molecular switch evolutionarily conserved in all gamma-herpesviruses. In previous studies, doxycycline-inducible Rta was shown to potently produce an irreversible G1 arrest followed by cellular senescence in 293 cells. Here, we demonstrate that in this system the inducible Rta not only reactivates resident genome of EBV but also that of Kaposi’s sarcoma-associated herpesvirus (KSHV), to similar efficiency. However, Rta-induced senescence program was terminated by the robust viral lytic cycle replication that eventually caused cell death. Furthermore, prior to the abrupt expression of immediate-early protein (EBV BZLF1 or KSHV RTA), Rta simultaneously down-regulates cell cycle activators (c-Myc, CDK6, CCND2) and up-regulates senescence-related genes (p21, 14-3-3s). Since Rta is a viral immediate-early transcriptional activator, it is envisioned that during the initial stage of viral reactivation, Rta may engage to modulate the host transcriptome, to halt cell cycle progression, and to maintain an ideal environment for manufacturing infectious virions. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE24585: Expression profiling of host genes modulated by Epstein-Barr virus (EBV) Rta in HEK293 cells GSE24586: Expression profiling of host genes modulated by Epstein-Barr virus Rta in nasopharyngeal carcinoma cells
2011-03-31 | E-GEOD-24587 | biostudies-arrayexpress