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 numerous cellular processes. Increasing evidence suggests that some lncRNAs function in immunity through various complex mechanisms. However, implication of a large fraction of lncRNAs in antiviral innate immunity remains uncharacterized. Here, we identified a lncRNA called lncRNA IFITM4P that was transcribed from interferon induced transmembrane protein 4 pseudogene (IFITM4P) , a pseudogene belonging to interferon induced transmembrane protein (IFITM) family. We found that expression of lncRNA IFITM4P was significantly induced by infection with several viruses including influenza A virus (IAV). Importantly, lncRNA IFITM4P acted as a positive regulator of innate antiviral immunity. Ectopic expression of lncRNA IFITM4P significantly suppressed IAV replication in vitro , whereas IFITM4P deficiency promoted the viral production. We further observed that expression of lncRNA IFITM4P was up-regulated by interferon (IFN) signaling during viral infection, and altering the expression of this lncRNA had significant effects on the mRNA levels of several IFITM family members including IFITM1, IFITM2 and IFITM3. Moreover, it was identified that lncRNA IFITM4P was a target of miR-24-3p that represses mRNA of IFITM1, IFITM2 and IFITM3. The experiments demonstrated that lncRNA IFITM4P was able to cross-regulate the expression of IFITM family members as a competing endogenous RNA (ceRNA), leading to increased stability of these IFITM mRNAs. Together, our results reveal that lncRNA IFITM4P, as a ceRNA, is involved in innate immunity against viral infection through the lncRNA IFITM4P-miR-24-3p- IFITM1/2/3 regulatory network. IMPORTANCE LncRNAs play important roles in various biological processes, but their involvement in host antiviral responses remains largely unknown. In this study, we revealed that the pseudogene IFITM4P belonging to IFITM family can transcribe a functional long noncoding RNA termed lncRNA IFITM4P. Importantly, results showed that lncRNA IFITM4P was involved in innate antiviral immunity, which resembles some interferon-stimulated genes (ISGs). Furthermore, lncRNA IFITM4P was identified as a target of miR-24-3p and acts as a ceRNA to inhibit the replication of IAV through regulating the mRNA levels of IFITM1, IFITM2 and IFITM3. These data provide a new insight into the role of a previously uncharacterized lncRNA encoded by a pseudogene in the host antiviral response, and a better understanding of the IFITM antiviral network.