title: AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.
abstract: Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Micco
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Gianluca
authors.initials: G
authors.lastname: Frera
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lugrin
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; INSERM, U1111, Center for Infectiology Research, Lyon 69007, France;
authors.forename: Yvan
authors.initials: Y
authors.lastname: Jamilloux
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907-2084;
authors.forename: Erh-Ting
authors.initials: ET
authors.lastname: Hsu
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Aude
authors.initials: A
authors.lastname: De Gassart
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Léa
authors.initials: L
authors.lastname: Zaffalon
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Bojan
authors.initials: B
authors.lastname: Bujisic
authors.affiliation: Flow Cytometry Facility, Ludwig Center for Cancer Research, University of Lausanne, Epalinges 1066, Switzerland;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Siegert
authors.affiliation: Protein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland;
authors.forename: Manfredo
authors.initials: M
authors.lastname: Quadroni
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland;
authors.forename: Petr
authors.initials: P
authors.lastname: Broz
authors.affiliation: INSERM, U1111, Center for Infectiology Research, Lyon 69007, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Henry
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907-2084; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907-2084.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Hrycyna
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; fabio.martinon@unil.ch.
authors.forename: Fabio
authors.identifier: 0000-0002-6969-822X
authors.initials: F
authors.lastname: Martinon
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D058847:Inflammasomes / Q000187:drug effects* / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology; D019888:Nelfinavir / Q000494:pharmacology*; D009685:Nuclear Envelope / Q000187:drug effects* / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000502:physiology
chemical_list: D053468:CARD Signaling Adaptor Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1; D004247:DNA; D020170:Caspase 1; D019888:Nelfinavir
keywords: DNA sensors; Nelfinavir; inflammasome; nuclear envelope stress; zmpste24