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

Cell Res. 2019 Aug;29(8):641-654. doi: 10.1038/s41422-019-0193-0. Epub 2019 Jun 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dogs
  • Female
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Madin Darby Canine Kidney Cells
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Phosphorylation
  • RAW 264.7 Cells
  • RNA, Long Noncoding
  • Rhabdoviridae Infections / immunology*
  • Rhabdoviridae Infections / virology
  • Vesicular stomatitis Indiana virus / immunology*

Substances

  • 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