title: Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming.
abstract: A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co-deletion of the essential executioners of mitochondrial apoptosis BAK and BAX, nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP3 inflammasome function. In contrast, caspase-8, a caspase essential for death-receptor-mediated apoptosis, is required for efficient Toll-like-receptor-induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP3 activation, and highlight an important non-apoptotic role for caspase-8 in regulating inflammasome activation and pro-inflammatory cytokine levels.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Ramanjaneyulu
authors.initials: R
authors.lastname: Allam
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Eric Chi-Wang
authors.initials: EC
authors.lastname: Yu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Mildenhall
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Donia M
authors.initials: DM
authors.lastname: Moujalled
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Rowena S
authors.initials: RS
authors.lastname: Lewis
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Francine
authors.initials: F
authors.lastname: Ke
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Kylie D
authors.initials: KD
authors.lastname: Mason
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: White
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Katryn J
authors.initials: KJ
authors.lastname: Stacey
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Warren
authors.initials: W
authors.lastname: Alexander
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia vince@wehi.edu.au.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D053181:Caspase 8 / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063306:Mitophagy / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051193:Toll-Like Receptors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D051193:Toll-Like Receptors; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D053181:Caspase 8; D021983:Cyclophilins
keywords: NLRP3; apoptosis; caspase‐8; inflammasome; mitochondria