The Mitochondrial Shuttle Protein ERAL1 Amplifies Antiviral Immune Responses

Mitochondrion not only serves as a platform for innate immune signaling transduction, but also acts as an accelerator to boost antiviral responses. The DNA and RNA released by mitochondrion can amplify type I IFNs induction. However, whether mitochondrial matrix proteins could be liberated out and involved in immune responses remains enigmatic. Here we use proximity-based labeling technology and identify the mitochondrial protein, ERAL1, as a MAVS interacting protein. ERAL1 deficiency can markedly reduce the downstream antiviral signaling triggered by RNA viruses. And ERAL1-deficient mice were more likely to die from RNA virus infection than wild-type mice. After virus infection, ERAL1 was released from mitochondria through BAX/BAK pore. The cytosolic ERAL1 positively regulated the RIG-I signaling by recruiting the E3 ubiquitin ligase TRIM25 to RIG-I, further facilitated RIG-I K63-linked polyubiquitination and downstream MAVS polymerization.