Self-Recognition of an Inducible Host lncRNA by RIG-I Feedback Restricts Innate Immune Response

• Published in: Cell Vol. 173; no. 4; pp. 906 - 919.e13
• Main Authors: Jiang, Minghong, Zhang, Shikun, Yang, Zongheng, Lin, Hongyu, Zhu, Jun, Liu, Lun, Wang, Wendie, Liu, Shuo, Liu, Wei, Ma, Yuanwu, Zhang, Lianfeng, Cao, Xuetao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03-05-2018
• Subjects: Animals; DEAD Box Protein 58 - metabolism; HEK293 Cells; Humans; immune homeostasis; Immunity, Innate; innate immunity; Interferon-alpha - metabolism; Interferon-beta - metabolism; lncRNA; Macrophages - cytology; Macrophages - immunology; Macrophages - virology; Mice; Mice, Inbred C57BL; non-self RNA; pathogenic dsRNA; Protein Binding; RAW 264.7 Cells; RIG-I; RNA Interference; RNA, Double-Stranded - metabolism; RNA, Long Noncoding - antagonists & inhibitors; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Small Interfering - metabolism; self regulation; Signal Transduction; type I interferons; Vesiculovirus - pathogenicity; lncRNA; innate immunity; pathogenic dsRNA; non-self RNA; RIG-I; self regulation; immune homeostasis; type I interferons
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.03.064

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.
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•lnc-Lsm3b competes with viral RNA for binding but stabilizing inactive RIG-I•Deficiency of lnc-Lsm3b specifically enhances RIG-I-initiated IFN production•Structural motifs of lnc-Lsm3b are vital for its optimal binding to RIG-I proteins•lnc-Lsm3b acts as a decoy for RIG-I and prevents downstream signaling
A self-recognition mode between RIG-I and an inducible host lncRNA functions to restrict innate immune response in a feedback manner.