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.
复制标题
新型 lncRNA linc-AhRA 负向调节小鼠小胶质细胞在嗜神经性疱疹病毒感染后的先天抗病毒反应
作者：
Wang Y;Luo W;Huang L;Xiao J;Song X;Li F;Ma Y;Wang X;Jin F;Liu P;Zhu Y;Kitazato K;Wang Y;Ren Z
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.
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影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
DOI：
10.1093/bioinformatics/btt495
发表时间：
2013-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Agostini F;Zanzoni A;Klus P;Marchese D;Cirillo D;Tartaglia GG
通讯作者：
Tartaglia GG
影响因子：
16.6
作者：
Aubert, Martine;Strongin, Daniel E.;Jerome, Keith R.
通讯作者：
Jerome, Keith R.
影响因子：
16.6
作者：
Hudson, William H.;Pickard, Mark R.;de Vera, Ian Mitchelle S.;Kuiper, Emily G.;Mourtada-Maarabouni, Mirna;Conn, Graeme L.;Kojetin, Douglas J.;Williams, Gwyn T.;Ortlund, Eric A.
通讯作者：
Ortlund, Eric A.
影响因子：
9.8
作者：
He L;Vanlandewijck M;Mäe MA;Andrae J;Ando K;Del Gaudio F;Nahar K;Lebouvier T;Laviña B;Gouveia L;Sun Y;Raschperger E;Segerstolpe Å;Liu J;Gustafsson S;Räsänen M;Zarb Y;Mochizuki N;Keller A;Lendahl U;Betsholtz C
通讯作者：
Betsholtz C