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

A recent study has uncovered a previously unknown function of the Dicer enzyme in fueling inflammation stemming from self-derived double-stranded RNAs (self-dsRNAs). Self-dsRNAs are generated through defects in RNA editing, splicing, epigenetic silencing, or mitochondrial RNA degradation, and can activate the immune system, leading to a condition known as autoinflammation.

The researchers identified a previously unappreciated role for Dicer in the processing of self-dsRNAs, as well as the necessity of the LGP2 protein for this inflammatory response. Importantly, Dicer's activity is distinct from its well-known role in microRNA biogenesis, as it enables the conversion of short, structurally constrained self-dsRNAs into immunostimulatory ligands.

This conversion occurs through Dicer binding to the self-dsRNAs and using its catalytic activity to generate shorter duplexes with accessible ends. These shorter duplexes are then available for binding by LGP2, which facilitates the assembly of MDA5 filaments, a key player in triggering inflammation.

The findings reveal a broad requirement for Dicer and LGP2 in the inflammatory response to self-dsRNAs, and the process is observed across multiple cell types, including a human stem cell-derived model of neuroinflammation. The study demonstrates that Dicer can transform short, constrained self-dsRNAs into strong inflammatory signals, effectively acting as a link between defective RNA processing and the activation of the immune system.