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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.

SUBMITTER: Ouyang J

PROVIDER: S-EPMC7104942 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription.

Ouyang Jing J Zhu Xiaomei X Chen Yuhai Y Wei Haitao H Chen Qinghuang Q Chi Xiaojuan X Qi Baomin B Zhang Lianfeng L Zhao Yi Y Gao George Fu GF Wang Guoshun G Chen Ji-Long JL

Cell host & microbe 20141112 5

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 ...[more]

PMID: 25525793

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Project description: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 an lncRNA called lncRNA IFITM4P that was transcribed from interferon-induced transmembrane protein 4 pseudogene (IFITM4P), a pseudogene belonging to the 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 viral production. We further observed that expression of lncRNA IFITM4P was upregulated 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, lncRNA IFITM4P was identified as a target of the microRNA miR-24-3p, which 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 the 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 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.

Dataset Information

NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription.

Publications

NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription.

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