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

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: GSE214663 | GEO | 2023/11/29

REPOSITORIES: GEO

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

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.

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

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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).

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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.

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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).

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SFPQ interacted proteins in HEK293T nucleus and cytoplasm

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

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).

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

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Combating viral contaminants in CHO cells by engineering innate immunity

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2019-05-31 | GSE119379 | GEO

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