1. Academic Validation
  2. A novel lncRNA linc-AhRA negatively regulates innate antiviral response in murine microglia upon neurotropic herpesvirus infection

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

  • Theranostics. 2021 Sep 21;11(19):9623-9651. doi: 10.7150/thno.64880.
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
Affiliations

Affiliations

  • 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.
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., FPKMHSV-1/FPKMCells.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; TBK1; TRIM27; aryl hydrocarbon receptor (AhR); conserved fragment; long non-coding RNA; neurotropic virus.

Figures
Products