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Researchers identified specific endogenous double-stranded RNAs (dsRNAs) that trigger immune responses by isolating and sequencing RNA from cellular MDA5 filaments. They found that over 84% of dsRNAs requiring both DDX3X helicase and ADAR1 editing for suppression were present in MDA5 filaments, compared to less than 1% of RNAs edited by ADAR1 alone. The immunogenic dsRNAs primarily consisted of inverted repeats in 3-prime-UTRs with high complementarity and longer intervening sequences, and these same RNAs showed hyperediting in DDX3X-mutant cancers.
Why it matters
This work reveals which self-RNAs can inappropriately activate the immune system when regulatory mechanisms fail, helping explain autoimmune conditions linked to ADAR1 deficiency. Understanding these quality control pathways could inform therapeutic strategies for autoimmune diseases and improve cancer immunotherapy approaches that exploit immune activation.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
ADAR1 converts adenosine to inosine in endogenous double-stranded RNAs (dsRNAs) to prevent excessive MDA5-driven interferon-stimulated gene expression. The source of endogenous immunogenic dsRNAs remains enigmatic because only a small fraction of ADAR1 substrates activate MDA5, and cellular MDA5 filaments have not been isolated. Here, we couple affinity purification of cellular MDA5 filaments with RNA sequencing to define immunogenic endogenous dsRNAs. Greater than 84% of dsRNAs suppressed by combined DDX3X RNA helicase and ADAR1 base-editing activities were present in MDA5 filaments, compared to less than 1% of dsRNA substrates acted on by ADAR1 alone. Dual substrate dsRNAs consisted of inverted repeats embedded in 3-prime-UTRs with high base-pair complementarity and longer intervening sequences between repeats, with a minor contribution coming from intermolecular dsRNAs formed by sense and antisense transcripts. Moreover, the majority of dual substrate immunogenic dsRNAs were hyperedited in DDX3X mutant cancers. This reveals the identity of endogenous immunogenic dsRNAs and quality control mechanisms underlying their suppression.
Source: Identification of highly immunogenic endogenous dsRNAs from cellular MDA5 filaments