Abstract
Mitochondria not only serve as a platform for innate immune signaling transduction but also enhance immune responses by releasing mitochondrial DNA and RNA into the cytoplasm. However, whether mitochondrial matrix proteins could be liberated and involved in immune responses remains enigmatic. Here, we identify the mitochondrial protein ERA G-protein-like 1 (ERAL1) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein by using proximity-based labeling technology. ERAL1 deficiency markedly reduces the downstream antiviral signaling triggered by RNA viruses. Moreover, ERAL1-deficient mice are more susceptible to lethality following RNA virus infection than wild-type mice. After virus infection, ERAL1 is released from mitochondria through the BAX/BAK pore. The cytosolic ERAL1 facilitates lysine 63 (K63)-linked ubiquitination of retinoicacid inducible gene-1 (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) and promotes downstream MAVS polymerization, thus positively regulating antiviral responses.