Retinoic acid‐inducible gene I (RIG‐I) and melanoma differentiation‐associated gene 5 (MDA5) are cytoplasmic sensors crucial for recognizing different species of viral RNAs, which triggers the production of type I interferons (IFNs) and inflammatory cytokines. Here, we identify RING finger protein 123 (RNF123) as a negative regulator of RIG‐I and MDA5. Overexpression of RNF123 inhibits IFN‐β production triggered by Sendai virus (SeV) and encephalomyocarditis picornavirus (EMCV). Knockdown or knockout of endogenous RNF123 potentiates IFN‐β production triggered by SeV and EMCV, but not by the sensor of DNA viruses cGAS. RNF123 associates with RIG‐I and MDA5 in both endogenous and exogenous cases in a viral infection‐inducible manner. The SPRY and coiled‐coil, but not the RING, domains of RNF123 are required for the inhibitory function. RNF123 interacts with the N‐terminal CARD domains of RIG‐I/MDA5 and competes with the downstream adaptor VISA/MAVS/IPS‐1/Cardif for RIG‐I/MDA5 CARD binding. These findings suggest that RNF123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG‐I and MDA5, a function that does not depend on its E3 ligase activity.
The human RING finger family protein RNF123 inhibits RNA virus‐induced IFN‐β production independent of its E3 ubiquitin ligase activity by interacting with the CARD domains of RIG‐I/MDA5, thereby competing with the RIG‐I/MDA5 signaling adaptor VISA.
hRNF123 inhibits innate antiviral signaling mediated by the RNA virus sensors RIG‐I/MDA5, but not by the DNA virus sensor cGAS.
hRNF123 interacts with the CARD domain of RIG‐I/MDA5, thereby inhibiting RLR‐VISA binding.
The inhibitory function of RNF123 does not rely on its E3 ligase activity and is not conserved in mouse cells.
- Received November 4, 2015.
- Revision received May 9, 2016.
- Accepted May 19, 2016.
- © 2016 The Authors