SLIRP mediates nuclear-mitochondrial communication during antiviral signaling to promote robust interferon response

Viral and endogenous double-stranded RNAs (dsRNAs) are recognized by cytosolic sensors and initiate antiviral signaling as a part of innate responses. Recent studies reveal a close association between mitochondrial dsRNAs (mt-dsRNAs) and several immune-related diseases. 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 a key amplifier of mt-dsRNA-triggered antiviral signals in the setting of an autoimmune condition and viral infection. We find that the activation of melanoma differentiation- associated gene 5 (MDA5) by dsRNAs upregulates SLIRP expression and facilitates its mitochondrial import. SLIRP then stabilizes mt-dsRNAs and promotes their cytosolic release where they further activate MDA5 to amplify the antiviral signaling, augmenting the interferon response. Interestingly, downregulation of cytosolic mt-dsRNAs by targeted knockdown of SLIRP or blocking mt-dsRNA release from mitochondria dampens the interferon response and increases cell vulnerability to certain viral infections. Furthermore, we find elevated SLIRP expression in monocytes of autoimmune patients, and downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in patients’ primary cells. Our study unveils amplified positive feedback of antiviral signaling through the stabilization of mt- dsRNAs by SLIRP, which promotes a robust interferon response.