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MDA5 guards against infection by surveying cellular RNA homeostasis [I]

ABSTRACT: MDA5 is an innate immune RNA sensor that detects a range of viruses. MDA5’s RNA agonists are not well defined. We used individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands. Surprisingly, upon infection with SARS-CoV-2 or encephalomyocarditis virus (EMCV), MDA5 bound overwhelmingly to cellular RNAs. Many binding sites were intronic and proximal to Alu elements. MDA5-bound RNA was enriched in Poly(A) and Poly(U) motifs, some of which may form double-stranded RNA. In EMCV-infected cells, cytoplasmic levels of intron-containing unspliced transcripts were increased, suggesting dysregulation of splicing. Concomitantly, MDA5 iCLIP peaks were enriched in introns accumulating in the cytoplasm of infected cells. Moreover, rescue of splicing abrogated MDA5 activation. Finally, depletion of viral RNA from RNA extracted from infected cells did not diminish its MDA5-stimulatory potential. Taken together, MDA5 surveys RNA processing fidelity and detects splicing perturbation during infection, establishing a paradigm of innate immune ‘guarding’ for RNA sensors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211240 | GEO | 2023/11/29

REPOSITORIES: GEO

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MDA5 guards against infection by surveying cellular RNA homeostasis [II]

Project description:MDA5 is an innate immune RNA sensor that detects a range of viruses. MDA5’s RNA agonists are not well defined. We used individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands. Surprisingly, upon infection with SARS-CoV-2 or encephalomyocarditis virus (EMCV), MDA5 bound overwhelmingly to cellular RNAs. Many binding sites were intronic and proximal to Alu elements. MDA5-bound RNA was enriched in Poly(A) and Poly(U) motifs, some of which may form double-stranded RNA. In EMCV-infected cells, cytoplasmic levels of intron-containing unspliced transcripts were increased, suggesting dysregulation of splicing. Concomitantly, MDA5 iCLIP peaks were enriched in introns accumulating in the cytoplasm of infected cells. Moreover, rescue of splicing abrogated MDA5 activation. Finally, depletion of viral RNA from RNA extracted from infected cells did not diminish its MDA5-stimulatory potential. Taken together, MDA5 surveys RNA processing fidelity and detects splicing perturbation during infection, establishing a paradigm of innate immune ‘guarding’ for RNA sensors.

2023-11-29 | GSE214663 | GEO

Integrative structure determination of an 85-kilodalton PTBP1-IRES complex in solution reveals a strong compaction with pronounced conformational flexibility

Project description:Cross-linking of isotope-labelled RNA coupled with mass spectrometry (CLIR-MS) was used to study the interaction between the four RNA recognition motifs (RRMs) of the protein PTBP1 with the internal ribosome entry site (IRES) of encephalomyocarditis virus (EMCV). These results are a reanalysis of PXD005566, with a broader parameter set.

2023-10-24 | PXD034894 | Pride

Differential gene expression in spinal cords from uninfected WT mice and infected RdRP transgenic mice (2 days post infection with Encephalomyocarditis Virus, EMCV)

Project description:Previously, we reported that mice made transgenic for a picornaviral RdRP â the 3Dpol protein of Theilerâs murine encephalomyelitis virus (TMEV) â suppress infection by diverse viral families. How the picornaviral RdRP transgene exerted antiviral protection in vivo was not known. To investigate the molecular mechanism, we determined gene expression profiles in spinal cords of WT and RdRP transgenic mice prior to (baseline) and after (2 days) infection with Encephalomyocarditis Virus (EMCV). Spinal cords from adult age-matched WT mice were harvested prior to (baseline) viral infection and RdRP transgenic spinal cords were harvested after (2 days) infection with Encephalomyocarditis Virus (EMCV). Total RNA was isolated (Qiagen RNeasy kit) and used as a template to synthesize biotinylated cRNA which was then hybridized to the HT Mouse Genome 430 2.0 GeneChip Array (Affymetrix).

2015-11-08 | E-GEOD-62757 | biostudies-arrayexpress

Comparative proteomics of extracellular vesicles derived from wildtype or mutant EMCV-infected cells

Project description:Non-enveloped viruses, such as picornaviruses, can escape infected host cells via release in extracellular vesicles (EVs) prior to the induction of lysis. These EVs cloak the secreted virus particles in a host-derived membrane, which alters virus-host interactions that affect infection efficiency and antiviral immunity. Currently, little is known about the viral and host factors regulating the formation and release of EV-enclosed viruses. The encephalomyocarditis virus (EMCV), belonging to the family of picornaviruses, expresses a Leader protein that targets various host cell processes. In this study, LC-MS/MS proteomic analysis was performed on EVs isolated via density gradient-based separation from HeLa cells infected with wildtype or Leader-deficient EMCV. Proteomes of these EVs were compared and proteins incorporated in EVs in a Leader-dependent manner were subjected to functional enrichment analysis and protein-interaction analysis.

2022-06-02 | PXD033906 | Pride

Differential gene expression in spinal cords from WT mice during uninfected (baseline) conditions and after (2 days post) infection with Encephalomyocarditis Virus (EMCV)

Project description:Previously, we reported that mice made transgenic for a picornaviral RdRP â the 3Dpol protein of Theilerâs murine encephalomyelitis virus (TMEV) â suppress infection by diverse viral families. How the picornaviral RdRP transgene exerted antiviral protection in vivo was not known. To investigate the molecular mechanism, we determined gene expression profiles in spinal cords of WT and RdRP transgenic mice prior to (baseline) and after (2 days) infection with Encephalomyocarditis Virus (EMCV). Spinal cords from adult age-matched, sex-matched WT mice were harvested prior to (baseline) and after (2 days post) EMCV viral infection. Total RNA was isolated (Qiagen RNeasy kit) and used as a template to synthesize biotinylated cRNA which was then hybridized to the HT Mouse Genome 430 2.0 GeneChip Array (Affymetrix).

2015-11-08 | E-GEOD-62758 | biostudies-arrayexpress

SFPQ interacted proteins in HEK293T nucleus and cytoplasm

Project description:Splicing factor proline and glutamine rich (SFPQ), DNA- and RNA binding protein, is crucial in various nuclear processes, including paraspeckle formation, miRNA synthesis and specially in transcription regulation. In addition, SFPQ play a role in the innate immune response to viruses, including DNA and RNA viruses. However, the connections between SFPQ and EMCV infection remain unclear. Here we report that the SFPQ is essential for EMCV replication. Depletion of SFPQ impairs EMCV production, while forced expression of SFPQ could promote viral replication. Mechanistically, EMCV inhibited viral RNA-mediated type I IFN and IL6 production to eliminate host antiviral immune responses. Cellular SFPQ was cleaved by the EMCV proteinase then entered the cytoplasm and interacted with other ribosomal proteins to facilitate its internal ribosome entry site (IRES)-dependent translation. Moreover, loss of SFPQ may impress host translation related gene expression and thus facilitate the EMCV replication. Altogether, our work provides a possible target for resisting EMCV or EMCV-like virus’s infection.

2019-01-10 | PXD011865 | Pride

Differential gene expression in spinal cords from WT mice during uninfected (baseline) conditions and after (2 days post) infection with Encephalomyocarditis Virus (EMCV)

Project description:Previously, we reported that mice made transgenic for a picornaviral RdRP – the 3Dpol protein of Theiler’s murine encephalomyelitis virus (TMEV) – suppress infection by diverse viral families. How the picornaviral RdRP transgene exerted antiviral protection in vivo was not known. To investigate the molecular mechanism, we determined gene expression profiles in spinal cords of WT and RdRP transgenic mice prior to (baseline) and after (2 days) infection with Encephalomyocarditis Virus (EMCV).

2015-11-08 | GSE62758 | GEO

Differential gene expression in spinal cords from uninfected WT mice and infected RdRP transgenic mice (2 days post infection with Encephalomyocarditis Virus, EMCV)

2015-11-08 | GSE62757 | GEO

Differential gene expression in spinal cords from WT and transgenic RdRP mice during uninfected (baseline) conditions

2015-11-08 | GSE62756 | GEO

Combating viral contaminants in CHO cells by engineering innate immunity

Project description:Viral contamination in biopharmaceutical manufacturing can lead to shortages in the supply of critical therapeutics. To facilitate the protection of bioprocesses, we explored the basis for the susceptibility of CHO cells, the most commonly used cell line in biomanufacturing, to RNA virus infection. Upon infection with certain ssRNA and dsRNA viruses, CHO cells fail to generate a significant interferon (IFN) response. Nonetheless, the downstream machinery for generating IFN responses and its antiviral activity is intact in these cells: treatment of cells with exogenously-added type I IFN or poly I:C prior to infection limited the cytopathic effect from Vesicular stomatitis virus (VSV), Encephalomyocarditis virus (EMCV), and Reovirus-3 virus (Reo) in a STAT1-dependent manner. To harness the intrinsic antiviral mechanism, we used RNA-Seq to identify two upstream repressors of STAT1: Gfi1 and Trim24. By knocking out these genes, the engineered CHO cells exhibited increased resistance to the prototype RNA viruses tested. Thus, omics-guided engineering of mammalian cell culture can be deployed to increase safety in biotherapeutic protein production.

2019-05-31 | GSE119379 | GEO

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