IGF2BP3 amplifies antiviral innate immunity with implications for autoimmune diseases

The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a known N6-methyladenosine (m6A) reader, but its role in antiviral innate immunity is unknown. Here, we identify IGF2BP3 as a critical positive regulator of antiviral responses. Viral infection and interferon (IFN) stimulation upregulate IGF2BP3, establishing a feedforward loop that potentiates virus-induced activation of the TBK1-IRF3 and NF-{kappa}B pathways, thereby amplifying type I interferon (IFN-I) production, and restricting viral replication in human and murine cells and in vivo. Mechanistically, IGF2BP3 directly binds and stabilizes MAVS and TBK1 mRNAs and promotes their translation by facilitating recruitment to the eIF4F/PABP-associated initiation complex. Upon infection, IGF2BP3 relocalizes to antiviral stress granules (avSGs), where it scaffolds the RIG-I-G3BP1 complex to enhance viral RNA sensing. Notably, IGF2BP3 is aberrantly upregulated in patients with systemic lupus erythematosus (SLE) and in Trex1 knockout (KO) mice, and pharmacological inhibition by curcumol suppresses IFN-I-driven pathology and improves survival. Collectively, our findings establish IGF2BP3 as a central feedforward circuit that couples viral RNA sensing to the control of RNA stability and translation of key signaling molecules, and reveals its potential as a therapeutic target in interferon-associated autoimmune diseases.