The mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1beta activation

Vince, JE; De Nardo, D; Gao, W; Vince, AJ; Hall, C; McArthur, K; Simpson, D; Vijayaraj, S; Lindqvist, LM; Bouillet, P; Rizzacasa, MA; Man, SM; Silke, J; Masters, SL; Lessene, G; Huang, DCS; Gray, DHD; Kile, BT; Shao, F; Lawlor, KE

Author(s): Vince, JE; De Nardo, D; Gao, W; Vince, AJ; Hall, C; McArthur, K; Simpson, D; Vijayaraj, S; Lindqvist, LM; Bouillet, P; Rizzacasa, MA; Man, SM; Silke, J; Masters, SL; Lessene, G; Huang, DCS; Gray, DHD; Kile, BT; Shao, F; Lawlor, KE;
Details: Publication Year 2018-11-27,Volume 25,Issue #9,Page 2339-2353 e4
Journal Title: Cell Reports
Publication Type: Journal Article
Abstract: Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1beta. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1beta maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1beta maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1beta release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro-inflammatory signals and provide an explanation as to why IL-1beta activation is often associated with cellular stress, such as during chemotherapy.
Publisher: Cell Press
Research Division(s): Inflammation; Cell Signalling And Cell Death; Systems Biology And Personalised Medicine; Molecular Genetics Of Cancer; Chemical Biology; Cancer And Haematology
PubMed ID: 30485804
Publisher's Version: https://doi.org/10.1016/j.celrep.2018.10.103
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2018.10.103
NHMRC Grants: NHMRC/1101405, NHMRC/1145788, NHMRC/1099262, NHMRC/1078763, NHMRC/1046010, NHMRC/1051506, NHMRC/1127885, NHMRC/1052598, NHMRC/1141466, NHMRC/1016647, NHMRC/1090236, NHMRC/1107149, NHMRC/1042629, NHMRC/461221, NHMRC/1113133,
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Documents: VInce JE et al_Cell Reports 2018.pdf - (4.90MB, application/pdf)

Creation Date: 2018-12-18 02:54:33

Last Modified: 2018-12-18 04:07:50