Long noncoding RNAs (lncRNAs) are single-stranded RNA molecules longer than 200 nt that regulate many cellular processes. MicroRNA 155 host gene (MIR155HG) encodes the microRNA (miR)-155 that regulates various signalling pathways of innate and adaptive immune responses against viral infections. MIR155HG also encodes a lncRNA that we call lncRNA-155. Here, we observed that expression of lncRNA-155 was markedly upregulated during influenza A virus (IAV) infection both in vitro (several cell lines) and in vivo (mouse model). Interestingly, robust expression of lncRNA-155 was also induced by infections with several other viruses. Disruption of lncRNA-155 expression in A549 cells diminished the antiviral innate immunity against IAV. Furthermore, knockout of lncRNA-155 in mice significantly increased IAV replication and virulence in the animals. In contrast, overexpression of lncRNA-155 in human cells suppressed IAV replication, suggesting that lncRNA-155 is involved in host antiviral innate immunity induced by IAV infection. Moreover, we found that lncRNA-155 had a profound effect on expression of protein tyrosine phosphatase 1B (PTP1B) during the infection with IAV. Inhibition of PTP1B by lncRNA-155 resulted in higher production of interferon-beta (IFN-β) and several critical interferon-stimulated genes (ISGs). Together, these observations reveal that MIR155HG derived lncRNA-155 can be induced by IAV, which modulates host innate immunity during the virus infection via regulation of PTP1B-mediated interferon response. KEYWORDS influenza A virus, innate immunity, lncRNA, miR-155, MIR155HG, PTP1B List of Abbreviations: 293T, HEK293T/human embryonic kidney cells; A549, human lung epithelial cells; bic, B-cell Integration Cluster; CA/04, A/California/04/2009; DMEM, Dulbecco's modified Eagle's medium; dpi, days post infection; EV, empty vector; FBS, fetal bovine serum; HA, haemagglutination assay; h-lncRNA-155, human lncRNA-155; hpi, hours post infection; IFN, interferon; IFN-β, interferon-beta; IRF3, interferon regulatory factor 3; IRF7, interferon regulatory factor 7; ISGs, interferon-stimulated genes; KO, bic/miR-155 −/− knock out mice; LLC, mouse Lewis lung carcinoma cells; lncRNAs, long noncoding RNAs; NIH/3T3, mouse embryonic fibroblasts; MDA5, antimelanoma differentiation-associated gene 5; MDCK, Madin-Darby canine kidney cells; miR, microRNA; MIR155HG, miR-155 host gene; m-lncRNA-155, bic/mouse lncRNA-155; NP, IAV nucleoprotein; nt, nucleotide; NRAV, negative regulator of antiviral response;PFA, plaque formation assay; PR8, A/Puerto Rico/8/1934; pre-miR-155, precursor miRNA; pri-miRNA, primary-miRNA; PRRs, pattern recognition receptors; PTP1B, tyrosine-protein phosphatase nonreceptor type 1; RAW 264.7, mouse Abelson murine leukaemia virus transformed macrophages; SeV, Sendai virus; SHIP1, Src homology 2-containing inositol phosphatase 1;sh-luc, Sh-luciferase; shRNAs, short hairpin RNAs; siRNA, small interfering RNA; SOCS1, suppressor of cytokine signalling 1; SPF, specific pathogen free; STAT1, signal transducer a...

Long noncoding RNAs (lncRNAs) are involved in a diversity of biological processes. It is known that differential expression of thousands of lncRNAs occurs in host during influenza A virus (IAV) infection. However, only few of them have been well characterized. Here, we identified a lncRNA, named as interferon (IFN)-stimulated lncRNA (ISR), which can be significantly upregulated in response to IAV infection in a mouse model. A sequence alignment revealed that lncRNA ISR is present in mice and human beings, and indeed, we found that it was expressed in several human and mouse cell lines and tissues. Silencing lncRNA ISR in A549 cells resulted in a significant increase in IAV replication, whereas ectopic expression of lncRNA ISR reduced the viral replication. Interestingly, interferon-β (IFN-β) treatment was able to induce lncRNA ISR expression, and induction of lncRNA ISR by viral infection was nearly abolished in host deficient of IFNAR1, a type I IFN receptor. Furthermore, the level of IAV-induced lncRNA ISR expression was decreased either in retinoic acid-inducible gene I (RIG-I) knockout A549 cells and mice or by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) inhibitor treatment. Together, these data elucidate that lncRNA ISR is regulated by RIG-I-dependent signaling that governs IFN-β production during IAV infection, and has an inhibitory capacity in viral replication.