miR-26a-5p Activates Antiviral Innate Immunity via Direct Binding and Activation of RIG-I

Emerging evidence has revealed the critical roles of microRNAs (miRNAs) in the regulation of innate immune responses. Nevertheless, it remains poorly understood whether specific miRNAs can directly modulate retinoic acid-inducible gene I (RIG-I), a principal sensor of cytoplasmic viral RNA and a key initiator of antiviral innate immunity. In this study, we identified miR-26a-5p as a potent activator of the innate antiviral immune responses. Notably, this activation operates independently of the canonical miRNA pathways of translational repression and mRNA degradation. Instead, we demonstrated that miR-26a-5p exerts its immunostimulatory effects by specifically binding to the RIG-I receptor. RNA immunoprecipitation and RNA pull-down assays confirmed a direct physical interaction between miR-26a-5p and the RIG-I protein. Subsequent site-directed mutagenesis verified that an AU-rich motif is critical for miR-26a-5p-driven RIG-I activation. Viral challenge experiments demonstrated that miR-26a-5p confers broad-spectrum, RIG-I-dependent antiviral activity against both DNA viruses (herpes simplex virus type 1 and Kaposi's sarcoma-associated herpesvirus) and RNA viruses (influenza A virus and respiratory syncytial virus). Collectively, our study indicates that miR-26a-5p may serve as a ligand that binds to and activates the RIG-I receptor. This discovery uncovers a previously unrecognized mechanism through which host miRNAs regulate antiviral innate immunity.