RNF123 has an E3 ligase-independent function in RIG-I-like receptor-mediated antiviral signaling.

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are critical cytoplasmic sensors for viral RNA recognition.
• Activation of RIG-I and MDA5 initiates innate immune responses, including type I interferon (IFN) production.

Purpose of the Study:

• To identify novel regulators of RIG-I and MDA5 signaling pathways.
• To elucidate the role of RING finger protein 123 (RNF123) in innate antiviral immunity.

Main Methods:

• Overexpression and knockdown/knockout studies of RNF123.
• Interferon-beta (IFN-β) production assays using Sendai virus (SeV) and encephalomyocarditis picornavirus (EMCV).
• Co-immunoprecipitation assays to study protein-protein interactions between RNF123, RIG-I, and MDA5.

Main Results:

• RNF123 acts as a negative regulator of RIG-I and MDA5.
• Overexpression of RNF123 suppresses virus-induced IFN-β production, while RNF123 depletion enhances it.
• RNF123 interacts with RIG-I and MDA5, specifically with their CARD domains, and competes with VISA/MAVS/IPS-1/Cardif.

Conclusions:

• RNF123 is a novel inhibitor of RIG-I and MDA5-mediated innate antiviral signaling.
• The inhibitory function of RNF123 is independent of its E3 ligase activity and relies on its SPRY and coiled-coil domains.
• RNF123 represents a potential therapeutic target for modulating antiviral responses.