title: Caspase-1 activity affects AIM2 speck formation/stability through a negative feedback loop.
abstract: The inflammasome is an innate immune signaling platform leading to caspase-1 activation, maturation of pro-inflammatory cytokines and cell death. Recognition of DNA within the host cytosol induces the formation of a large complex composed of the AIM2 receptor, the ASC adaptor and the caspase-1 effector. Francisella tularensis, the agent of tularemia, replicates within the host cytosol. The macrophage cytosolic surveillance system detects Francisella through the AIM2 inflammasome. Upon Francisella novicida infection, we observed a faster kinetics of AIM2 speck formation in ASC(KO) and Casp1(KO) as compared to WT macrophages. This observation was validated by a biochemical approach thus demonstrating for the first time the existence of a negative feedback loop controlled by ASC/caspase-1 that regulates AIM2 complex formation/stability. This regulatory mechanism acted before pyroptosis and required caspase-1 catalytic activity. Our data suggest that sublytic caspase-1 activity could delay the formation of stable AIM2 speck, an inflammasome complex associated with cell death.
authors: International Center for Infectiology Research, Université de Lyon Lyon, France.
authors: C
authors: C
authors: Juruj
authors: V
authors: V
authors: Lelogeais
authors: R
authors: R
authors: Pierini
authors: M
authors: M
authors: Perret
authors: B F
authors: BF
authors: Py
authors: Y
authors: Y
authors: Jamilloux
authors: P
authors: P
authors: Broz
authors: F
authors: F
authors: Ader
authors: M
authors: M
authors: Faure
authors: T
authors: T
authors: Henry
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D005246:Feedback; D005604:Francisella tularensis / Q000276:immunology*; D017353:Gene Deletion; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; D020170:Caspase 1
keywords: AIM2; Francisella tularensis; caspase-1; inflammasome; regulation
references: Cell Death Differ. 2012 Oct;19(10):1709-21
references: 22555457
references: Nat Immunol. 2010 May;11(5):385-93
references: 20351693
references: Science. 2009 Feb 20;323(5917):1057-60
references: 19131592
references: J Immunol. 2009 Jul 15;183(2):787-91
references: 19570822
references: J Innate Immun. 2010;2(5):406-21
references: 20505309
references: J Med Microbiol. 2004 Oct;53(Pt 10):953-958
references: 15358816
references: Nat Immunol. 2012 Jan 29;13(3):255-63
references: 22286270
references: Semin Immunol. 2009 Aug;21(4):199-207
references: 19539499
references: PLoS One. 2012;7(11):e50473
references: 23185631
references: Nature. 2008 Nov 13;456(7219):264-8
references: 18849965
references: Autophagy. 2006 Oct-Dec;2(4):312-4
references: 16874073
references: Nat Immunol. 2008 Oct;9(10):1171-8
references: 18724372
references: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9771-6
references: 20457908
references: Autophagy. 2012 Sep;8(9):1342-56
references: 22863802
references: J Biol Chem. 2006 Nov 17;281(46):35217-23
references: 16984919
references: Nat Immunol. 2011 Jan;12(1):37-44
references: 21102435
references: J Innate Immun. 2012;4(1):16-30
references: 22067846
references: J Biol Chem. 2011 Sep 16;286(37):32513-24
references: 21757759
references: mBio. 2011 Sep 01;2(4):
references: 21771913
references: Nat Immunol. 2011 Mar;12(3):222-30
references: 21151103
references: J Exp Med. 2007 May 14;204(5):987-94
references: 17452523
references: Cell Host Microbe. 2010 May 20;7(5):412-9
references: 20417169
references: J Immunol. 2008 May 15;180(10):6885-91
references: 18453609
references: PLoS One. 2011;6(6):e20609
references: 21698237
references: Nature. 2006 Mar 9;440(7081):228-32
references: 16407890
references: Cell. 2006 Sep 22;126(6):1135-45
references: 16990137
references: Methods Enzymol. 2008;442:251-70
references: 18662574
references: Nat Immunol. 2010 May;11(5):395-402
references: 20351692
references: Cell Death Differ. 2007 Sep;14(9):1590-604
references: 17599095
references: Nature. 2004 Jul 8;430(6996):213-8
references: 15190255
references: Virulence. 2011 Jan-Feb;2(1):54-7
references: 21317555
references: Nature. 2011 Mar 17;471(7338):368-72
references: 21368762
references: Front Biosci (Landmark Ed). 2009 Jun 01;14:4836-47
references: 19482590
references: Nat Immunol. 2012 Mar 19;13(4):333-42
references: 22430786
references: Nature. 2009 Mar 26;458(7237):514-8
references: 19158675
references: PLoS One. 2011;6(10):e27040
references: 22046441
references: J Exp Med. 2012 Oct 22;209(11):1969-83
references: 23045604
references: J Exp Med. 2005 Oct 17;202(8):1043-9
references: 16230474
references: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9
references: 18230725
references: Cell Host Microbe. 2010 Dec 16;8(6):471-83
references: 21147462
references: Cell Microbiol. 2006 Nov;8(11):1812-25
references: 16824040
references: Sci Transl Med. 2011 May 11;3(82):82ra38
references: 21562230
references: Mol Cell. 2002 Aug;10(2):417-26
references: 12191486
references: Nature. 2011 Oct 16;479(7371):117-21
references: 22002608
references: Immunity. 2012 Apr 20;36(4):561-71
references: 22483801
references: J Biol Chem. 2004 Jun 4;279(23):24785-93
references: 15039421
references: Nat Chem Biol. 2012 Sep;8(9):745-7
references: 22797665
references: Nat Immunol. 2009 Mar;10(3):266-72
references: 19158679