title: Cell death is not essential for caspase-1-mediated interleukin-1β activation and secretion.
abstract: Caspase-1 cleaves and activates the pro-inflammatory cytokine interleukin-1 beta (IL-1β), yet the mechanism of IL-1β release and its dependence on cell death remains controversial. To address this issue, we generated a novel inflammasome independent system in which we directly activate caspase-1 by dimerization. In this system, caspase-1 dimerization induced the cleavage and secretion of IL-1β, which did not require processing of caspase-1 into its p20 and p10 subunits. Moreover, direct caspase-1 dimerization allowed caspase-1 activation of IL-1β to be separated from cell death. Specifically, we demonstrate at the single cell level that IL-1β can be released from live, metabolically active, cells following caspase-1 activation. In addition, we show that dimerized or endogenous caspase-8 can also directly cleave IL-1β into its biologically active form, in the absence of canonical inflammasome components. Therefore, cell death is not obligatory for the robust secretion of bioactive IL-1β.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Conos
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: K E
authors.initials: KE
authors.lastname: Lawlor
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: D L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Vince
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Lindqvist
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D027081:DNA Gyrase / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D011993:Recombinant Fusion Proteins; D053181:Caspase 8; D020170:Caspase 1; D027081:DNA Gyrase