The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation

James E. Vince, Dominic De Nardo, Wenqing Gao, Angelina J. Vince, Cathrine Hall, Kate McArthur, Daniel Simpson, Swarna Vijayaraj, Lisa M. Lindqvist, Philippe Bouillet, Mark A. Rizzacasa, Si Ming Man, John Silke, Seth L. Masters, Guillaume Lessene, David C.S. Huang, Daniel H.D. Gray, Benjamin T. Kile, Feng Shao, Kate E. Lawlor

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53 Citations (Scopus)

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-1β. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1β 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-1β maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1β 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-1β activation is often associated with cellular stress, such as during chemotherapy. BAX/BAK-mediated apoptosis is considered immunologically silent. Vince et al. show that in macrophages, MCL-1 and BCL-XL restrain BAX/BAK-induced pro-inflammatory IL-1β activation. IAP degradation and activation of caspase-3 and -7 downstream of BAX/BAK triggers caspase-8-mediated cleavage and activation of IL-1β and cause potassium ion efflux to trigger NLRP3 inflammasome formation.

Original languageEnglish
Pages (from-to)2339-2353
Number of pages15
JournalCell Reports
Volume25
Issue number9
DOIs
Publication statusPublished - 27 Nov 2018

Keywords

  • BAK
  • BAX
  • BCL-XL
  • caspase-1
  • caspase-8
  • Gasdermin
  • IAPs
  • MCL-1
  • mitochondria
  • NLRP3

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