A LncRNA-Encoded Interferon Memory Circuit Mediated by MDA5

Type I interferon (IFN) signaling is central to antiviral immunity and immune homeostasis, yet the mechanisms that sustain and amplify this response remain unclear. Here, we identify two IFN-inducible Alu-free lncRNAs, lnc-CCDC122 and CATIP-AS2, that amplify IFN responses through the cytosolic RNA sensor MDA5. These lncRNAs are induced downstream of IFNβ but exhibit delayed kinetics relative to canonical ISGs, suggesting a distinct regulatory role in sustaining signaling. Under prolonged type I IFN exposures, both transcripts were accumulated in senescent fibroblasts prior to the increase of Alu-containing RNA transcripts and were correlated with IFN signature intensity in PBMCs from systemic lupus erythematosus (SLE) patients. Mechanistically, lnc-CCDC122-2:1 and CATIP-AS2:2 prime MDA5 activation and promote antiviral gene expression kinetics, a function dependent on their cytoplasmic localization and RNA modification status. We found that both lncRNAs were m5C-modified and bound by the m5C reader ALY/REF, which facilitated their export and cytoplasmic accumulation. Disruption of ALY/REF or mutation of conserved m5C sites abolished their immunostimulatory function. Elevated levels of m5C-modified RNA in PBMCs from severe SLE patients further support a functional link. These findings uncover a novel class of regulatory lncRNAs whose m5C-dependent localization and signaling activity potentiate innate immune responses, highlighting an RNA modification–based mechanism for positive feedback in type I IFN signaling and offering potential targets for modulating IFN-driven pathology.