Dataset Information

The nuclear RNA exosome is co-opted to enhance host:viral RNA hybrids that propel influenza virus ribogenesis and infectivity

ABSTRACT: The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in exosome genes are associated with neurodegenerative diseases. Here, we show that transient depletion of nuclear RNA exosome subunits in epithelial cells inhibits influenza virus replication. Similarly, viral biogenesis was suppressed in cells derived from mice with conditional ablation of the RNA exosome subunit Exosc3. Furthermore, patient-derived cells with a congenital EXOSC3 mutation were less susceptible to influenza virus infection. Using proteomics and next generation sequencing during infection, we show that the viral polymerase complex (PA, PB2, PB1) co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3’ end degradation. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Overall, we discovered a critical nexus between an essential component of the influenza virus (polymerase) and an essential component of the cell (exosome), alteration of which leads to breakage of host-pathogen symmetry and a lose-lose scenario (viral impairment and neurodegeneration).

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE96677 | GEO | 2017/05/08

SECONDARY ACCESSION(S): PRJNA379330

REPOSITORIES: GEO

ACCESS DATA

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. This model is hosted on BioModels Database and identified by: MODEL1307270000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

The nuclear RNA exosome is co-opted to enhance host:viral RNA hybrids that propel influenza virus ribogenesis and infectivity

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure