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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Vince, James E. ; De Nardo, Dominic ; Gao, Wenqing ; Vince, Angelina J. ; Hall, Cathrine ; McArthur, Kate ; Simpson, Daniel ; Vijayaraj, Swarna ; Lindqvist, Lisa M. ; Bouillet, Philippe ; Rizzacasa, Mark A. ; Man, Si Ming ; Silke, John ; Masters, Seth L. ; Lessene, Guillaume ; Huang, David C.S. ; Gray, Daniel H.D. ; Kile, Benjamin T. ; Shao, Feng ; Lawlor, Kate E. / The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation. In: Cell Reports. 2018 ; Vol. 25, No. 9. pp. 2339-2353.
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title = "The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation",
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.",
keywords = "BAK, BAX, BCL-XL, caspase-1, caspase-8, Gasdermin, IAPs, MCL-1, mitochondria, NLRP3",
author = "Vince, {James E.} and {De Nardo}, Dominic and Wenqing Gao and Vince, {Angelina J.} and Cathrine Hall and Kate McArthur and Daniel Simpson and Swarna Vijayaraj and Lindqvist, {Lisa M.} and Philippe Bouillet and Rizzacasa, {Mark A.} and Man, {Si Ming} and John Silke and Masters, {Seth L.} and Guillaume Lessene and Huang, {David C.S.} and Gray, {Daniel H.D.} and Kile, {Benjamin T.} and Feng Shao and Lawlor, {Kate E.}",
year = "2018",
month = "11",
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language = "English",
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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 2018, 'The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation', Cell Reports, vol. 25, no. 9, pp. 2339-2353. https://doi.org/10.1016/j.celrep.2018.10.103

The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation. / Vince, James E.; De Nardo, Dominic; Gao, Wenqing; Vince, Angelina J.; Hall, Cathrine; McArthur, Kate; Simpson, Daniel; Vijayaraj, Swarna; Lindqvist, Lisa M.; Bouillet, Philippe; Rizzacasa, Mark A.; Man, Si Ming; Silke, John; Masters, Seth L.; Lessene, Guillaume; Huang, David C.S.; Gray, Daniel H.D.; Kile, Benjamin T.; Shao, Feng; Lawlor, Kate E.

In: Cell Reports, Vol. 25, No. 9, 27.11.2018, p. 2339-2353.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1β Activation

AU - Vince, James E.

AU - De Nardo, Dominic

AU - Gao, Wenqing

AU - Vince, Angelina J.

AU - Hall, Cathrine

AU - McArthur, Kate

AU - Simpson, Daniel

AU - Vijayaraj, Swarna

AU - Lindqvist, Lisa M.

AU - Bouillet, Philippe

AU - Rizzacasa, Mark A.

AU - Man, Si Ming

AU - Silke, John

AU - Masters, Seth L.

AU - Lessene, Guillaume

AU - Huang, David C.S.

AU - Gray, Daniel H.D.

AU - Kile, Benjamin T.

AU - Shao, Feng

AU - Lawlor, Kate E.

PY - 2018/11/27

Y1 - 2018/11/27

N2 - 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.

AB - 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.

KW - BAK

KW - BAX

KW - BCL-XL

KW - caspase-1

KW - caspase-8

KW - Gasdermin

KW - IAPs

KW - MCL-1

KW - mitochondria

KW - NLRP3

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DO - 10.1016/j.celrep.2018.10.103

M3 - Article

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SP - 2339

EP - 2353

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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