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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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