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

Abstract	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.
Authors	Yumei Zhou, Mengxuan Li, Yiquan Xue, Zhiqing Li, Weitao Wen, Xingguang Liu, Yuanwu Ma, Lianfeng Zhang, Zhongyang Shen, Xuetao Cao
Journal	Cell research (Cell Res) Vol. 29 Issue 8 Pg. 641-654 (08 2019) ISSN: 1748-7838 [Electronic] England
PMID	31213650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	IRF3 protein, human Interferon Regulatory Factor-3 Interferon Type I Irf3 protein, mouse LRRC55 protein, human Membrane Proteins RNA, Long Noncoding leucine-rich repeat-containing protein 55, mouse
Topics	Animals Dogs Female HEK293 Cells Humans Immunity, Innate Interferon Regulatory Factor-3 (genetics, metabolism) Interferon Type I (immunology, metabolism) Madin Darby Canine Kidney Cells Male Membrane Proteins (genetics, metabolism) Mice Mice, Knockout NIH 3T3 Cells Phosphorylation RAW 264.7 Cells RNA, Long Noncoding Rhabdoviridae Infections (immunology, virology) Vesicular stomatitis Indiana virus (immunology)

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