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. image The human RING finger family protein RNF 123 inhibits RNA virus‐induced IFN ‐β production independent of its E3 ubiquitin ligase activity by interacting with the CARD domains of RIG ‐I/ MDA 5, thereby competing with the RIG ‐I/ MDA 5 signaling adaptor VISA . hRNF 123 inhibits innate antiviral signaling mediated by the RNA virus sensors RIG ‐I/ MDA 5, but not by the DNA virus sensor cGAS . hRNF 123 interacts with the CARD domain of RIG‐I / MDA 5, thereby inhibiting RLR ‐ VISA binding. The inhibitory function of RNF 123 does not rely on its E3 ligase activity and is not conserved in mouse cells.