Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation
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ABSTRACT:
PROVIDER: PRJNA414051 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral double-stranded RNA (dsRNA) sensor that induces antiviral immune response. We here demonstrate that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNA because its filament formation on dsRNA is impaired by the imperfect duplex structure, AGS-variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNA. Moreover, we identified an unexpected role of RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context-dependence of self vs. non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 to recognize dsRNA comes at a cost of self-recognition, and implicates a unique role of Alu RNAs as virus-like elements that shape the primate immune system.
2018-01-29 | GSE104864 | GEO
Project description:Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral double-stranded RNA (dsRNA) sensor that induces antiviral immune response. We here demonstrate that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNA because its filament formation on dsRNA is impaired by the imperfect duplex structure, AGS-variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNA. Moreover, we identified an unexpected role of RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context-dependence of self vs. non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 to recognize dsRNA comes at a cost of self-recognition, and implicates a unique role of Alu RNAs as virus-like elements that shape the primate immune system.
2018-01-29 | GSE103539 | GEO
Project description:Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [ADAR1KO HEK293T and WT MDA5]
| PRJNA414057 | ENA
Project description: Not available
| S-EPMC5807104 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-01-29 | GSE104865 | GEO
Project description:An extrachromosomal replication system was established to examine the perturbation of Alu-carrying genes in response to elevated Alu RNAs in the opposite direction. The null hypothesis is that the Alu-carrying RNA duplex cannot trigger subsequent post-transcriptional regulation, manifesting a random perturbation of expression levels. Comparing HEK293 cells transfected and not-transfected with pDR2-Alu vectors.
2013-05-13 | E-GEOD-39822 | biostudies-arrayexpress
Project description:An extrachromosomal replication system was established to examine the perturbation of Alu-carrying genes in response to elevated Alu RNAs in the opposite direction. The null hypothesis is that the Alu-carrying RNA duplex cannot trigger subsequent post-transcriptional regulation, manifesting a random perturbation of expression levels.
2013-05-13 | GSE39822 | GEO
Project description:Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation [WT HEK293T and mutant MDA5]
| PRJNA401809 | ENA
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
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 | GSE211240 | GEO