IRF3-binding lncRNA-ISIR strengthens interferon production in viral infection and autoinflammation

Cell Rep. 2021 Nov 2;37(5):109926. doi: 10.1016/j.celrep.2021.109926.

Abstract

Interferon regulatory factor 3 (IRF3) is an essential transductor for initiation of many immune responses. Here, we show that lncRNA-ISIR directly binds IRF3 to promote its phosphorylation, dimerization, and nuclear translocation, along with enhanced target gene productions. In vivo lncRNA-ISIR deficiency results in reduced IFN production, uncontrolled viral replication, and increased mortality. The human homolog, AK131315, also binds IRF3 and promotes its activation. More important, AK131315 expression is positively correlated with type I interferon (IFN-I) level and severity in patients with lupus. Mechanistically, in resting cells, IRF3 is bound to suppressor protein Flightless-1 (Fli-1), which keeps its inactive state. Upon infection, IFN-I-induced lncRNA-ISIR binds IRF3 at DNA-binding domain in cytoplasm and removes Fli-1's association from IRF3, consequently facilitating IRF3 activation. Our results demonstrate that IFN-I-inducible lncRNA-ISIR feedback strengthens IRF3 activation by removing suppressive Fli-1 in immune responses, revealing a method of lncRNA-mediated modulation of transcription factor (TF) activation.

Keywords: autoimmunity; infection; innate immunology; long noncoding RNA; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Gene Silencing
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism*
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism*
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Proto-Oncogene Protein c-fli-1 / metabolism
  • RAW 264.7 Cells
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Vero Cells
  • Vesicular Stomatitis / genetics
  • Vesicular Stomatitis / immunology
  • Vesicular Stomatitis / metabolism*
  • Vesicular Stomatitis / virology
  • Vesicular stomatitis Indiana virus / immunology
  • Vesicular stomatitis Indiana virus / pathogenicity

Substances

  • FLI1 protein, human
  • Fli1 protein, mouse
  • IRF3 protein, human
  • Ifnar1 protein, mouse
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Proto-Oncogene Protein c-fli-1
  • RNA, Long Noncoding
  • Receptor, Interferon alpha-beta