Mitochondrial translocation of immunostimulatory RNA RN7SL1 suppresses innate immune responses

The significance of mitochondria in innate immunity is increasingly recognized. Mitochondrial immunostimulatory nucleic acids released into the cytosol can trigger an innate immune response. However, the possibility of translocating immunostimulatory nucleic acids from the cytosol to the mitochondria remains unexplored. In this study, we demonstrate that the nuclear-encoded immunostimulatory RNA RN7SL1 could be translocated into the mitochondria from the cytosol. Once inside the mitochondria, RN7SL1 is shielded by mitochondrial membranes, which prevents its recognition by cytosolic dsRNA sensors. The RNA-binding protein LRPPRC interacts with RN7SL1 directly and regulates its translocation. Inhibition of LRPPRC impairs this translocation, reduces RN7SL1 abundance in mitochondria, and activates the RIG-I-dependent innate immune response. Furthermore, in clinical human lung cancer specimens, elevated RN7SL1 expression is associated with a more pronounced negative correlation between the immune response and LRPPRC expression. These findings reveal a novel mitochondrial function in suppressing the immune response induced by immunostimulatory RNA.