title: Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.
abstract: The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines interleukin 1β (IL-1β) and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella tularensis subspecies novicida (F. novicida). The activation of AIM2 by F. novicida requires bacteriolysis, yet whether this process is accidental or is a host-driven immunological mechanism has remained unclear. By screening nearly 500 interferon-stimulated genes (ISGs) through the use of small interfering RNA (siRNA), we identified guanylate-binding proteins GBP2 and GBP5 as key activators of AIM2 during infection with F. novicida. We confirmed their prominent role in vitro and in a mouse model of tularemia. Mechanistically, these two GBPs targeted cytosolic F. novicida and promoted bacteriolysis. Thus, in addition to their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria.
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Meunier
authors.affiliation: CIRI, Inserm U1111, CNRS UMR 5308, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallet
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Roland F
authors.initials: RF
authors.lastname: Dreier
authors.affiliation: CIRI, Inserm U1111, CNRS UMR 5308, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Costanzo
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Leonie
authors.initials: L
authors.lastname: Anton
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rühl
authors.affiliation: SFR Biosciences, UMS344/US8, Inserm, CNRS, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dussurgey
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Mathias S
authors.initials: MS
authors.lastname: Dick
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Kistner
authors.affiliation: CIRI, Inserm U1111, CNRS UMR 5308, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Rigard
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Degrandi
authors.affiliation: Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.affiliation: Department of Microbiology and Immunology, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: CIRI, Inserm U1111, CNRS UMR 5308, Université Claude Bernard Lyon-1, Ecole Normale Supérieure, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Henry
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Petr
authors.initials: P
authors.lastname: Broz
mesh_terms: D000818:Animals; D001433:Bacteriolysis; D002478:Cells, Cultured; D003600:Cytosol / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005604:Francisella tularensis / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D014406:Tularemia / Q000276:immunology*
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D034741:RNA, Small Interfering; C534329:GBP2 protein, human; D019204:GTP-Binding Proteins; C472531:Gbp5 protein, mouse