RNF 123 has an E3 ligase‐independent function in RIG ‐I‐like receptor‐mediated antiviral signaling

Retinoic acid‐inducible gene I ( RIG ‐I) and melanoma differentiation‐associated gene 5 ( MDA 5) are cytoplasmic sensors crucial for recognizing different species of viral RNA s, which triggers the production of type I interferons ( IFN s) and inflammatory cytokines. Here, we identify RING finger protein 123 ( RNF 123) as a negative regulator of RIG ‐I and MDA 5. Overexpression of RNF 123 inhibits IFN ‐β production triggered by Sendai virus (SeV) and encephalomyocarditis picornavirus ( EMCV ). Knockdown or knockout of endogenous RNF 123 potentiates IFN ‐β production triggered by SeV and EMCV , but not by the sensor of DNA viruses cGAS . RNF 123 associates with RIG ‐I and MDA 5 in both endogenous and exogenous cases in a viral infection‐inducible manner. The SPRY and coiled‐coil, but not the RING , domains of RNF 123 are required for the inhibitory function. RNF 123 interacts with the N‐terminal CARD domains of RIG ‐I/ MDA 5 and competes with the downstream adaptor VISA / MAVS / IPS ‐1/Cardif for RIG ‐I/ MDA 5 CARD binding. These findings suggest that RNF 123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG ‐I and MDA 5, a function that does not depend on its E3 ligase activity.