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

Abstract

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 in vitro or in vivo 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.IMPORTANCE 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.

A Long Noncoding RNA Regulates Hepatitis C Virus Infection Through Interferon Alpha–Inducible Protein 6

“…lncRNA‐CMPK2/NRIR (Negative Regulator of the IFN Response) inhibits HCV replication through transcriptional down‐regulation of several ISGs in a Jak‐Stat‐dependent manner. lncRNA NEAT1 controls Hantavirus infection through the RIG‐I/IRF7 pathway . In this study, we found that IFN induces both lncRNA IFI6 and IFI6 expression, the latter of which exerts major inhibitory effects on HCV infection.…”

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

“…On the other hand, DDX60 cannot detect a 63-nucleotide 5 0 triphosphated ssRNA, indicating that this helicase is unable to recognize viral RNA that undergoes 5 0 triphosphate capping [81]. Further studies have also found that Hantaan virus (HNTV) inhibits the transcription of DDX60, but the long noncoding RNA NEAT1 can interfere with these inhibitory effects and thereby deploy DDX60 to counter the HNTV infection [84]. Moreover, the expression of DDX60 is altered during human papillomavirus (HPV) infection in HaCaT cells.…”

Toll‐like receptors, long non‐coding RNA NEAT1, and RIG‐I expression are associated with HBeAg‐positive chronic hepatitis B patients in the active phase

“…7 In addition to the importance of TLRs and RIG-I in the immune response, recently increasing evidence has also confirmed the crucial roles of long non-coding RNAs (lncRNAs) profile in modulating host innate immunity during viral infection as well. 8,9 One of the lncRNAs, nuclear-enriched abundant transcript 1(NEAT1), was recently known as a virus-induced lncRNA (VINC) and was considered to be critical for the immune response against virus, however different virus infection, the different expression of NEAT1 observed. [8][9][10] LncRNA NEAT1 expression is upregulated after Hantaan virus (HTNV), HIV-1 infection, and HSV-1 infection, whereas it is downregulated upon Zika virus infection.…”

“…8,9 One of the lncRNAs, nuclear-enriched abundant transcript 1(NEAT1), was recently known as a virus-induced lncRNA (VINC) and was considered to be critical for the immune response against virus, however different virus infection, the different expression of NEAT1 observed. [8][9][10] LncRNA NEAT1 expression is upregulated after Hantaan virus (HTNV), HIV-1 infection, and HSV-1 infection, whereas it is downregulated upon Zika virus infection. [8][9][10][11] But the roles of NEAT1 in HBV infection, especially the innate immunity of chronic HBV infection at the active phase, are currently unclear.…”

“…[8][9][10] LncRNA NEAT1 expression is upregulated after Hantaan virus (HTNV), HIV-1 infection, and HSV-1 infection, whereas it is downregulated upon Zika virus infection. [8][9][10][11] But the roles of NEAT1 in HBV infection, especially the innate immunity of chronic HBV infection at the active phase, are currently unclear.…”