title: The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection.
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.
authors.affiliation: 1] Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia.
authors.forename: Si Ming
authors.identifier: 0000000250792857
authors.initials: SM
authors.lastname: Man
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Karki
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: R K Subbarao
authors.initials: RK
authors.lastname: Malireddi
authors.affiliation: Hartwell Center for Bioinformatics &Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Microbiology and Immunology, Osaka University, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: 1] Department of Medical Protein Research, Vlaams Instituut voor Biotechnologie, Ghent, Belgium. [2] Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Mohamed
authors.identifier: 0000000248987663
authors.initials: M
authors.lastname: Lamkanfi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D001433:Bacteriolysis / Q000235:genetics; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology; D004269:DNA, Bacterial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005604:Francisella tularensis / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D058847:Inflammasomes / Q000378:metabolism*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000378:metabolism; D014406:Tularemia / Q000276:immunology*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D019204:GTP-Binding Proteins; D058847:Inflammasomes; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D009713:Nucleotidyltransferases; C540422:Aim2 protein, mouse; C494258:Irf1 protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase