摘要：SummaryLong noncoding RNAs (lncRNAs) participate in host antiviral responses; however, how viruses exploit host lncRNAs for immune evasion remains largely unexplored. Functional screening of differentially expressed lncRNA profile in patients infected with influenza A virus (IAV) revealed that lncNSPL (Gene Symbol: LOC105370355) was highly expressed in monocytes. Deregulated lncNSPL expression in infected monocytes significantly increased type I interferon (IFN-I) production and inhibited IAV replication. Moreover, lncNSPL overexpression in mice increased the susceptibility to IAV infection and impaired IFN-I production. LncNSPL directly bound to retinoic acid-inducible gene I (RIG-I) and blocked the interaction between RIG-I and E3 ligase tripartite interaction motif 25 (TRIM25), reducing TRIM25-mediated lysine 63 (K63)-linked RIG-I ubiquitination and limiting the downstream production of antiviral mediators during the late stage of IAV infection. Our findings provide mechanistic insights into the means by which lncNSPL promotes IAV replication and immune escape via restricting the TRIM25-mediated RIG-I K63-linked ubiquitination. Thus, lncNSPL may represent a promising pharmaceutical target for anti-IAV therapy.Graphical abstractDisplay OmittedHighlights•NS1 protein of Influenza A virus (IAV) promotes lncNSPL expression•Deficiency of lncNSPL specifically enhances retinoic acid-inducible gene I (RIG-I) initiated IFN production•lncNSPL competes with tripartite interaction motif 25 (TRIM25) for binding RIG-I and inhibits its K63 ubiquitination•lncNSPL inhibits innate antiviral immune responses and enhances viral replicationBiochemistry; Immunology; Virology
