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Theranostics 2021; 11(19):9623-9651. doi:10.7150/thno.64880 This issue Cite

Research Paper

A novel lncRNA linc-AhRA negatively regulates innate antiviral response in murine microglia upon neurotropic herpesvirus infection

Yiliang Wang^1,2,3,4, Weisheng Luo^1,2,3,4, Lianzhou Huang^1,2,3,4, Ji Xiao^1,2,3,4, Xiaowei Song^1,2,3,4, Feng Li^1,2,3,4, Yuying Ma^1,2,3,4, Xiaohui Wang^1,2,3,4, Fujun Jin^1,2,3,4, Ping Liu^1,2,3,4, Yexuan Zhu^1,2,3,4, Kaio Kitazato^5✉, Yifei Wang^1,2,3,4✉, Zhe Ren^1,2,3,4✉

1. Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
2. Key Laboratory of Virology of Guangdong province, Jinan University, Guangzhou, China.
3. Guangdong Province Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China.
4. Guangdong Provincial biotechnology drug & Engineering Technology Research Center, Jinan University, Guangzhou, China.
5. Department of Clinical Research Pharmacy, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.

✉ Corresponding authors: kkholiac.jp (Kaio Kitazato); rz62com (Zhe Ren); twang-yfcom (Yifei Wang).

Abstract

Microglia are the primary cellular source of type I interferons (I-IFNs) in the brain upon neurotropic virus infection. Although the I-IFN-based antiviral innate immune response is crucial for eliminating viruses, overproduction led to immune disorders. Therefore, the relatively long-lasting I-IFNs must be precisely controlled, but the regulatory mechanism for the innate antiviral response in microglia remains largely unknown. Long non-coding RNAs (lncRNAs) are being recognized as crucial factors in numerous diseases, but their regulatory roles in the innate antiviral response in microglia are undefined.

Methods: The high-throughput RNA sequencing was performed to obtain differentially expressed lncRNAs (DELs) in primary microglia infected with or without the neurotropic herpes simplex virus type 1 (HSV-1). We selected four DELs ranked in the top 15 in basic level and their fold change induced by HSV-1, i.e., FPKM_HSV-1/FPKM_Cells.We subsequently found a key lncRNA affecting the innate antiviral response of microglia significantly. We next used dual-luciferase reporter assays, bioinformatical tools, and truncation mutants of both lncRNA and targeted proteins to elucidate the downstream and upstream mechanism of action of lncRNA. Further, we established microglia-specific knock-in (KI) mice to investigate the role of lncRNA in vivo.

Results: We identified a long intergenic non-coding RNA, linc-AhRA, involved in regulating the innate antiviral response in murine microglia. linc-AhRA is activated by aryl hydrocarbon receptor (AhR) and restricts I-IFN production in microglia upon neurotropic herpesvirus infection and innate immune stimulation. Mechanistically, linc-AhRA binds to both tripartite motif-containing 27 (TRIM27) and TANK-binding kinase 1 (TBK1) through its conserved 117nt fragment as a molecular scaffold to enhance TRIM27-TBK1 interaction. This interaction facilitates the TRIM27-mediated ubiquitination of TBK1 and results in ubiquitin-proteasome-dependent degradation of TBK1. Consequently, linc-AhRA suppresses I-IFN production through facilitating TBK1 degradation and limits the microglial innate immune response against neurotropic herpesvirus infection. Microglia-specific KI of linc-AhRA mice shows a weakened antiviral immune response upon neurotropic herpesvirus challenge due to a reduction of TBK1 in microglia.

Conclusion: Our findings indicate that linc-AhRA is a negative regulator of I-IFN production in microglia to avoid excessive autoimmune responses. These findings uncover a previously unappreciated role for lncRNA conserved fragments in the innate antiviral response, providing a strong foundation for developing nucleotide drugs based on conserved functional fragments within lncRNAs.

Keywords: Microglia, neurotropic virus, long non-coding RNA, conserved fragment, TBK1, TRIM27, aryl hydrocarbon receptor (AhR)

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