SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases.

Abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor driving dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop-interacting RNA-binding protein (SLIRP) as an amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and the targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and elevates their cytosolic levels to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in primary cells of patients with autoimmune disease and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of the interferon response through positive feedback amplification of antiviral signaling via mt-dsRNAs.