NRAV, a Long Noncoding RNA, Modulates Antiviral Responses through Suppression of Interferon-Stimulated Gene Transcription

Abstract

Long noncoding RNAs (lncRNAs) modulate various biological processes, but their role in host antiviral responses is largely unknown. Here we identify a lncRNA as a key regulator of antiviral innate immunity. Following from the observation that a lncRNA that we call negative regulator of antiviral response (NRAV) was dramatically downregulated during infection with several viruses, we ectopically expressed NRAV in human cells or transgenic mice and found that it significantly promotes influenza A virus (IAV) replication and virulence. Conversely, silencing NRAV suppressed IAV replication and virus production, suggesting that reduction of NRAV is part of the host antiviral innate immune response to virus infection. NRAV negatively regulates the initial transcription of multiple critical interferon-stimulated genes (ISGs), including IFITM3 and MxA, by affecting histone modification of these genes. Our results provide evidence for a lncRNA in modulating the antiviral interferon response.

Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression

“…lncRNA-CMPK2, which is stimulated by IFN-α through the JAK-STAT pathway, suppresses the expression of ISGs such as IFIT3, ISG15, and IFITM1 (20). Influenza A virus-induced lncRNA (NRAV) inhibits the host response to viral infection by suppressing ISG expression (21). bone marrow stromal cell antigen 2 (BST2) IFN-stimulated positive regulator (BISPR) was identified as a positive regulator of BST2 expression (22,23).…”

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

“…To date, several lncRNAs have been shown to play an important role in the innate immune response against influenza virus and be associated with viral pathogenesis, including NRAV (negative regulator of antiviral response)[11], NEAT1 (nuclear enriched abundant transcript 1)[30], Bst2/BISPR (bone marrow stromal cell antigen 2 IFN-stimulated positive regulator) [31,32] and VIN (virus inducible lincRNA)[33]. NRAV inhibits the transcription of interferon-stimulated genes via affecting histone modification of these genes (mainly MxA and IFITM3), resulting in the manipulation of the antiviral response[11].…”

“…NRAV inhibits the transcription of interferon-stimulated genes via affecting histone modification of these genes (mainly MxA and IFITM3), resulting in the manipulation of the antiviral response[11]. The ectopic expression of human NRAV conferred the hypersensitivity of the mice to influenza virus infection, evidenced by higher virus titers in the lung, increased body weight loss and higher mortality[11]. In addition, the cooperative action between the transcriptional regulators and nuclear lncRNAs also impacts the innate immune response to IAV infection.…”

“…LncRNAs regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels in diverse biological contexts[6]. In addition, a variety of molecular mechanisms were used as major regulators of these function, such as modulating histone modifications[11], interfering the transcription [12,13], regulating patterns of alternative splicing [14,15],generating small RNAs[16], and modulating protein activation and localization[17]. …”

“…As far as we known, only a few lncRNAs, such as NRAV (negative regulator of antiviral response)[11], NEAT1 (nuclear enriched abundant transcript 1)[30], Bst2/BISPR (bone marrow stromal cell antigen 2 IFN-stimulated positive regulator) [31,32] and VIN (virus inducible lincRNA) [33] have been demonstrated to be associated with the innate immunity against influenza virus and viral pathogenesis. Therefore, studies are still needed to better understand the potential roles of other lncRNAs in the pathogenesis of influenza virus.…”