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

Abstract

Self-derived double-stranded RNA (self-dsRNA) acts as potent triggers of autoinflammation and damage-associated molecular patterns in cancer and infection. However, the upstream processes controlling self-dsRNA homeostasis remain unclear. We uncover a non-canonical role for human Dicer in driving cell-intrinsic immunity to self-dsRNAs that arise from editing or splicing defects, epigenetic deregulation or mitochondrial stress. Dicer loss abolishes type-I interferon induction, PKR activation, and OAS-RNase L activation in response to self - but not exogenous - dsRNA in multiple cell types, including a clinically-relevant hiPSC model of neuroinflammation. Dicer interacts with G3BP1 and LGP2 to regulate self-dsRNA availability and recognition, respectively, independently of miRNAs. As immunostimulatory self-dsRNAs fail to accumulate and activate dsRNA sensors in absence of Dicer, these findings position Dicer as a central regulator of self-dsRNA sensing.