title: Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation.
abstract: Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of caspase-8 and is required for macrophage survival. Recent studies have revealed a selective role of caspase-8 in noncanonical IL-1β production that is independent of caspase-1 or inflammasome. Here we demonstrated that c-FLIP(L) is an unexpected contributor to canonical inflammasome activation for the generation of caspase-1 and active IL-1β. Hemizygotic deletion of c-FLIP impaired ATP- and monosodium uric acid (MSU)-induced IL-1β production in macrophages primed through Toll-like receptors (TLRs). Decreased IL-1β expression was attributed to a reduced activation of caspase-1 in c-FLIP hemizygotic cells. In contrast, the production of TNF-α was not affected by downregulation in c-FLIP. c-FLIP(L) interacted with NLRP3 or procaspase-1. c-FLIP is required for the full NLRP3 inflammasome assembly and NLRP3 mitochondrial localization, and c-FLIP is associated with NLRP3 inflammasome. c-FLIP downregulation also reduced AIM2 inflammasome activation. In contrast, c-FLIP inhibited SMAC mimetic-, FasL-, or Dectin-1-induced IL-1β generation that is caspase-8-mediated. Our results demonstrate a prominent role of c-FLIP(L) in the optimal activation of the NLRP3 and AIM2 inflammasomes, and suggest that c-FLIP could be a valid target for treatment of inflammatory diseases caused by over-activation of inflammasomes.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Kuo
authors.affiliation: 1] Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan [2] Institute of Immunology, National Taiwan University, Taipei 10052, Taiwan.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: K-T
authors.initials: KT
authors.lastname: Yang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: S-T
authors.initials: ST
authors.lastname: Chen
authors.affiliation: National Laboratory Animal Center, National Applied Research Laboratories, Tainan 74147, Taiwan.
authors.forename: S-T
authors.initials: ST
authors.lastname: Jiang
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: C
authors.identifier: 0000000273794417
authors.initials: C
authors.lastname: Gordy
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Y-W
authors.initials: YW
authors.lastname: He
authors.affiliation: 1] Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan [2] Institute of Immunology, National Taiwan University, Taipei 10052, Taiwan.
authors.forename: M-Z
authors.initials: MZ
authors.lastname: Lai
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010455:Peptides; D015398:Signal Transduction
chemical_list: C410167:AIM2 protein, human; C540422:Aim2 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D010455:Peptides; C120583:transfecting peptide I