The Transcription Factor IRF1 and Guanylate-Binding Proteins Target Activation of the AIM2 Inflammasome by Francisella Infection

Nat Immunol. 2015 May;16(5):467-75. doi: 10.1038/ni.3118. Epub 2015 Mar 16.

Abstract

Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for sensing by AIM2 depending on the pathogen encountered by the cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteriolysis / genetics
  • Cells, Cultured
  • DNA / immunology
  • DNA, Bacterial / genetics
  • DNA-Binding Proteins / metabolism*
  • Francisella tularensis / physiology*
  • GTP-Binding Proteins / metabolism*
  • Gene Expression Regulation / genetics
  • Inflammasomes / metabolism*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Interferon Type I / metabolism
  • Mice
  • Mice, Knockout
  • Nucleotidyltransferases / metabolism
  • Tularemia / immunology*

Substances

  • Aim2 protein, mouse
  • DNA, Bacterial
  • DNA-Binding Proteins
  • Inflammasomes
  • Interferon Regulatory Factor-1
  • Interferon Type I
  • Irf1 protein, mouse
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • GTP-Binding Proteins

Associated data

  • GEO/GSE66461