The Long Noncoding RNA NEAT1 Exerts Antihantaviral Effects by Acting as Positive Feedback for RIG-I Signaling

Hantavirus infection, which causes zoonotic diseases with a high mortality rate in humans, has long been a global public health concern. Over the past decades, accumulating evidence suggests that long noncoding RNAs (lncRNAs) play key regulatory roles in innate immunity. However, the involvement of...

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Bibliographic Details
Published in:Journal of virology 2017-05, Vol.91 (9)
Main Authors: Ma, Hongwei, Han, Peijun, Ye, Wei, Chen, Hesong, Zheng, Xuyang, Cheng, Linfeng, Zhang, Liang, Yu, Lan, Wu, Xing'an, Xu, Zhikai, Lei, Yingfeng, Zhang, Fanglin
Format: Article
Language:English
Subjects:
A549 Cells
Animals
Cell Line, Tumor
Cellular Response to Infection
Chlorocebus aethiops
DEAD Box Protein 58 - metabolism
DEAD-box RNA Helicases - metabolism
Hantaan virus
Hantaan virus - genetics
Hantaan virus - growth & development
Hantaan virus - immunology
Hantavirus
Hantavirus Infections - immunology
Hantavirus Infections - virology
HEK293 Cells
HeLa Cells
Human Umbilical Vein Endothelial Cells
Humans
Immunity, Innate - genetics
Interferon-beta - biosynthesis
Male
Mice
Mice, Inbred C57BL
PTB-Associated Splicing Factor - metabolism
Receptors, Immunologic
RNA Interference
RNA, Long Noncoding - biosynthesis
RNA, Long Noncoding - genetics
RNA, Small Interfering - genetics
Signal Transduction - genetics
Vero Cells
Virus Replication - genetics
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Summary:Hantavirus infection, which causes zoonotic diseases with a high mortality rate in humans, has long been a global public health concern. Over the past decades, accumulating evidence suggests that long noncoding RNAs (lncRNAs) play key regulatory roles in innate immunity. However, the involvement of host lncRNAs in hantaviral control remains uncharacterized. In this study, we identified the lncRNA NEAT1 as a vital antiviral modulator. NEAT1 was dramatically upregulated after Hantaan virus (HTNV) infection, whereas its downregulation or delayed host innate immune responses and aggravated HTNV replication. Ectopic expression of NEAT1 enhanced beta interferon (IFN-β) production and suppressed HTNV infection. Further investigation suggested that NEAT1 served as positive feedback for RIG-I signaling. HTNV infection activated NEAT1 transcription through the RIG-I-IRF7 pathway, whereas NEAT1 removed the transcriptional inhibitory effects of the splicing factor proline- and glutamine-rich protein (SFPQ) by relocating SFPQ to paraspeckles, thus promoting the expression of RIG-I and DDX60. RIG-I and DDX60 had synergic effects on IFN production. Taken together, our findings demonstrate that NEAT1 modulates the innate immune response against HTNV infection, providing another layer of information about the role of lncRNAs in controlling viral infections. Hantaviruses have attracted worldwide attention as archetypal emerging pathogens. Recently, increasing evidence has highlighted long noncoding RNAs (lncRNAs) as key regulators of innate immunity; however, their roles in hantavirus infection remain unknown. In the present work, a new unexplored function of lncRNA NEAT1 in controlling HTNV replication was found. NEAT1 promoted interferon (IFN) responses by acting as positive feedback for RIG-I signaling. This lncRNA was induced by HTNV through the RIG-I-IRF7 pathway in a time- and dose-dependent manner and promoted HTNV-induced IFN production by facilitating RIG-I and DDX60 expression. Intriguingly, NEAT1 relocated SFPQ and formed paraspeckles after HTNV infection, which might reverse inhibitive effects of SFPQ on the transcription of RIG-I and DDX60. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA NEAT1 in host innate immunity after HTNV infection. In summary, our findings provide additional insights regarding the role of lncRNAs in controlling viral infections.
ISSN:0022-538X
1098-5514
DOI:10.1128/jvi.02250-16