A noncanonical function of Dicer fuels self-dsRNA-driven inflammation

Dicer’s noncanonical catalytic activity enables self-derived dsRNAs to activate MDA5, PKR, and OAS-RNase L, converting structurally constrained self-dsRNAs into immunostimulatory ligands.

• Why it matters: Self-dsRNAs can trigger autoinflammation, but the structural steps that make constrained self-dsRNAs immunostimulatory are unclear.
• What they did: In multiple cell types, including a human stem cell-derived neuroinflammation model, Dicer is required for self-dsRNA responses from defects in RNA editing, splicing, epigenetic silencing, or mitochondrial RNA degradation, independently of microRNA biogenesis.
• The result: Dicer binds immunostimulatory dsRNAs and cleaves them into shorter duplexes with accessible ends for LGP2 end-binding, enabling MDA5 filament assembly and danger-signal recognition.

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