Interferon-inducible cytoplasmic lncLrrc55-AS promotes antiviral innate responses by strengthening IRF3 phosphorylation

• Published in: Cell research 2019-08, Vol.29 (8), p.641-654
• Main Authors: Zhou, Yumei, Li, Mengxuan, Xue, Yiquan, Li, Zhiqing, Wen, Weitao, Liu, Xingguang, Ma, Yuanwu, Zhang, Lianfeng, Shen, Zhongyang, Cao, Xuetao
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/21; 13/89; 14/19; 38/71; 38/77; 631/250/262; 631/337/384/2568; 64/60; 96/95; Animals; Biomedical and Life Sciences; Cell Biology; Deactivation; Demethylation; Dogs; Feedback loops; Female; HEK293 Cells; Humans; Immune response; Immune system; Immunity; Immunity, Innate; Inactivation; Innate immunity; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferon Type I - immunology; Interferon Type I - metabolism; Life Sciences; Madin Darby Canine Kidney Cells; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; NIH 3T3 Cells; Non-coding RNA; Phosphatase; Phosphorylation; Positive feedback; RAW 264.7 Cells; Rhabdoviridae Infections - immunology; Rhabdoviridae Infections - virology; RNA, Long Noncoding; Signaling; Vesicular stomatitis Indiana virus - immunology; Viruses
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/s41422-019-0193-0

Type I interferon (IFN-I) production is efficiently induced to ensure a potent innate immune response to viral infection. How this response can be enhanced, however, remains to be explored. Here, we identify a new cytoplasmic long non-coding RNA (lncRNA), lncLrrc55-AS, that drives a positive feedback loop to promote interferon regulatory factor 3 (IRF3) signaling and IFN-I production. We show that lncLrrc55-AS is virus-induced in multiple cell types via the IFN-JAK-STAT pathway. LncLrrc55-AS-deficient mice display a weakened antiviral immune response and are more susceptible to viral challenge. Mechanistically, lncLrrc55-AS binds phosphatase methylesterase 1 (PME-1), and promotes the interaction between PME-1 and the phosphatase PP2A, an inhibitor of IRF3 signaling. LncLrrc55-AS supports PME-1-mediated demethylation and inactivation of PP2A, thereby enhancing IRF3 phosphorylation and signaling. Loss of PME-1 phenocopies lncLrrc55-AS deficiency, leading to diminished IRF3 phosphorylation and IFN-I production. We have identified an IFN-induced lncRNA as a positive regulator of IFN-I production, adding mechanistic insight into lncRNA-mediated regulation of signaling in innate immunity and inflammation.