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.

线粒体不仅作为先天免疫信号转导的平台，而且通过将线粒体 DNA 和 RNA 释放到细胞质中来增强免疫反应。然而，线粒体基质蛋白是否可以被释放并参与免疫反应仍然是个谜。在这里，我们通过使用基于邻近的标记技术将线粒体蛋白 ERA G 蛋白样 1 (ERAL1) 鉴定为线粒体抗病毒信号蛋白 (MAVS) 相互作用蛋白。ERAL1 缺陷显着降低了由 RNA 病毒触发的下游抗病毒信号传导。此外，ERAL1 缺陷小鼠比野生型小鼠更容易受到 RNA 病毒感染后的致死率。病毒感染后，ERAL1 通过 BAX/BAK 孔从线粒体中释放出来。