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Abstract
The innate RNA sensor RIG-I is critical in the initiation of antiviral type I interferons
(IFNs) production upon recognition of "non-self" viral RNAs. Here, we identify a host-derived,
IFN-inducible long noncoding RNA, lnc-Lsm3b, that can compete with viral RNAs in the
binding of RIG-I monomers and feedback inactivate the RIG-I innate function at late
stage of innate response. Mechanistically, binding of lnc-Lsm3b restricts RIG-I protein's
conformational shift and prevents downstream signaling, thereby terminating type I
IFNs production. Multivalent structural motifs and long-stem structure are critical
features of lnc-Lsm3b for RIG-I binding and inhibition. These data reveal a non-canonical
self-recognition mode in the regulation of immune response and demonstrate an important
role of an inducible "self" lncRNA acting as a potent molecular decoy actively saturating
RIG-I binding sites to restrict the duration of "non-self" RNA-induced innate immune
response and maintaining immune homeostasis, with potential utility in inflammatory
disease management.