title: 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 downregulationin vitroorin vivodelayed 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.IMPORTANCEHantaviruses 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.
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Peijun
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Hesong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Center of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Xing'an
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China yflei@fmmu.edu.cn flzhang@fmmu.edu.cn.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Microbiology, Fourth Military Medical University, Xi'an, China yflei@fmmu.edu.cn flzhang@fmmu.edu.cn.
authors.forename: Fanglin
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D057809:HEK293 Cells; D018063:Hantaan virus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D018778:Hantavirus Infections / Q000276:immunology* / Q000821:virology; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016899:Interferon-beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072670:PTB-Associated Splicing Factor / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics; D014709:Vero Cells; D014779:Virus Replication / Q000235:genetics
chemical_list: C577276:NEAT1 long non-coding RNA, human; D000072670:PTB-Associated Splicing Factor; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D016899:Interferon-beta; C452820:RIGI protein, human; C561888:DDX60 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
keywords: DDX60; Hantaan virus; NEAT1; RIG-I; SFPQ; beta interferon; innate immunity; interferons; long noncoding RNA