PNMA4 enhances anti-RNA virus immunity by promoting RIG-I signaling pathway

Mitochondria play a crucial role as a hub for innate immune signal transduction, with mitochondrial antiviral signaling protein (MAVS) being a key regulator in the activation of interferon-β (IFN-β) production. It is essential for MAVS to initiate innate antiviral responses against RNA viruses, contributing to the host's defense mechanisms. In this study, we identified the mitochondrial protein Paraneoplastic Ma Family 4 (PNMA4/MOAP1) as a MAVS-interacting protein by using proximity-based labeling technology in THP-1 and discovered that it could enhance retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) signaling pathway. The absence of PNMA4 significantly reduced RNA virus-induced activation of antiviral pathways and made Pnma4^-/- mice more susceptible to infection. On the one hand, PNMA4 enhanced the interaction between RIG-I and MAVS after RNA virus infection. On the other hand, it facilitated RIG-I lysine 63 (K63)-linked polyubiquitination at lysine 657 by TRIM25, thus positively regulating antiviral responses.