lncRNAs regulate the innate immune response to viral infection

Advanced Review

Jing Ouyang, Jiayue Hu, Ji‐Long Chen

Published Online: Dec 15 2015

DOI: 10.1002/wrna.1321

Full article on Wiley Online Library: HTML PDF

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Long noncoding RNAs (lncRNAs) are extensively expressed in mammalian cells and play a crucial role as RNA regulators in various cellular processes. Increasing data reveal that they function in innate antiviral immunity through complex mechanisms. Thousands of lncRNAs are regulated by RNA virus or DNA virus infection. The significant differential expression of lncRNAs is induced by virus or host antiviral signaling mediated by interferons (IFNs) and tumor necrosis factor‐α. In turn, these lncRNAs modulate the host immune response including the pathogen recognition receptor (PRR)‐related signaling, the translocation and activation of transcription factors, the production of IFNs and cytokines, the IFN‐activated JAK‐STAT signaling and the transcription of antiviral IFN‐stimulated genes (ISGs). Using gain‐ or loss‐of‐function analysis, the effect of lncRNAs on viral replication has been investigated to elucidate the essential role of lncRNA in the host–virus interaction. lncRNAs have shown specifically elevated or decreased levels in patients with viral diseases, suggesting the possibility of clinical application as biomarkers. Here we review the current advances of viral infection‐associated host lncRNAs, their functional significance in different aspects of antiviral immune response, the specific mechanisms and unsolved issues. We also summarize the regulation of lncRNAs by viruses, PRR agonists and cytokines. In addition, virus‐encoded lncRNAs and their functional involvement in host–virus interaction are addressed. WIREs RNA 2016, 7:129–143. doi: 10.1002/wrna.1321 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease

Host lncRNAs regulate multiple steps of the antiviral innate immune response. Upon viral invasion, host cell starts the PRR signaling cascade, which further activates the transcription factors and initiates the expression of cytokines. After binding with corresponding receptors, cytokines trigger the receptor‐associated signaling and the production of antiviral proteins, such as ISG proteins. Some cytoplasmic or nuclear lncRNAs can increase or inhibit the activities of transcription factors, which are listed in the upper dashed red rectangle. Other nuclear lncRNAs can modulate the transcription of cytokines or antiviral genes (ISGs), which are listed in the lower dashed red rectangle.

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Host lncRNAs regulate the transcription of cytokines and IFN‐stimulated genes (ISGs) as a modulator of histone modification, promoter activation or repression. NeST interacts with WDR5 to increase the chromatin open modifications at the ifng loci. THRIL increases TNF‐α transcription via binding with hnRNP L on the TNF‐α promoter. NEAT1 sequesters the repressor SFPQ in the paraspeckle and thus increases the IL‐8 transcription. lincRNA‐Cox2 increases IL‐6 via an unknown mechanism and decreases the CCL5 transcription by interaction with hnRNP A/B and hnRNP A2/B1. NRAV as a repressive factor decrease the expression of several critical ISGs through modulation of histone modification. lncRNA‐CMPK2 functions as a repressor via an IFN‐independent unknown mechanism.

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Host lncRNAs regulate the transcription factor activities as a scaffold, decoy or posttranslational modification shield. NRON inhibits the activation/dephosphorylation of NFAT as a component of the scaffold complex. Lethe interacts with RelA to repress the transcription activity of NF‐κB. lnc‐DC directly binds with STAT3, prevents the dephosphorylation of STAT3 by SHP1, and activates STAT3‐dependent transcription.

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