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

Self-derived double-stranded RNAs (self-dsRNAs) can drive autoinflammation, but how structurally constrained self-dsRNAs become immunostimulatory remains unclear. We identify a noncanonical role for Dicer and a broad requirement for LGP2 in this process. Dicer is required for responses to self-dsRNAs, but not exogenous dsRNAs, that arise from defects in RNA editing, splicing, epigenetic silencing, or mitochondrial RNA degradation in multiple cell types, including a human stem cell-derived model of neuroinflammation. Independently of microRNA biogenesis, Dicer promotes activation of MDA5, PKR, and OAS-RNase L. Dicer binds immunostimulatory dsRNAs and uses its catalytic activity to generate shorter duplexes with accessible ends that are available for LGP2 end-binding, enabling MDA5 filament assembly. Thus, Dicer converts short, structurally constrained self-dsRNAs into inflammatory ligands, thereby facilitating their recognition as danger-associated signals.