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


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.

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We thank Dr. Pin Wang for technical assistance. This work is supported by grants from the National Natural Science Foundation of China (81788101 to X.C.), the National Key Research & Development Program of China (2018YFA0507403 to X.C.), and CAMS Innovation Fund for Medical Sciences (2016-12M-1-003 to X.C.).

Author information

X.C. designed and supervised the research; Y.Z., M.L., Y.X., Z.L., W.W. and X.L. performed the experiments; Y.M. and L.Z. generated KO mice; Z.S. provided reagents; X.C. and Y.Z. analyzed the data and wrote the manuscript.

Correspondence to Xuetao Cao.

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The authors declare no competing interests.

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