title: AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC.
abstract: Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed pyroptosis. Here we show that AIM2 and NLRP3 inflammasomes activate caspase-8 and -1, leading to both apoptotic and pyroptotic cell death. The AIM2 inflammasome is activated by cytosolic DNA. The balance between pyroptosis and apoptosis depended upon the amount of DNA, with apoptosis seen at lower transfected DNA concentrations. Pyroptosis had a higher threshold for activation, and dominated at high DNA concentrations because it happens more rapidly. Gene knockdown showed caspase-8 to be the apical caspase in the AIM2- and NLRP3-dependent apoptotic pathways, with little or no requirement for caspase-9. Procaspase-8 localised to ASC inflammasome 'specks' in cells, and bound directly to the pyrin domain of ASC. Thus caspase-8 is an integral part of the inflammasome, and this extends the relevance of the inflammasome to cell types that do not express caspase-1.
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
authors: V
authors: V
authors: Sagulenko
authors: S J
authors: SJ
authors: Thygesen
authors: D P
authors: DP
authors: Sester
authors: A
authors: A
authors: Idris
authors: J A
authors: JA
authors: Cridland
authors: P R
authors: PR
authors: Vajjhala
authors: T L
authors: TL
authors: Roberts
authors: K
authors: K
authors: Schroder
authors: J E
authors: JE
authors: Vince
authors: J M
authors: JM
authors: Hill
authors: J
authors: J
authors: Silke
authors: K J
authors: KJ
authors: Stacey
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins; D058847:Inflammasomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; D034741:RNA, Small Interfering; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D053181:Caspase 8; D053453:Caspase 9; D020170:Caspase 1
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