Active MLKL triggers the NLRP3 inflammasome in a cell intrinsic manner

Conos, Stephanie A. , Chen, Kaiwen W. , De Nardo, Dominic , Hara, Hideki , Whitehead, Lachlan , Núñez, Gabriel , Masters, Seth L. , Murphy, James M. , Schroder, Kate , Vaux, David L. , Lawlor, Kate E. , Lindqvist, Lisa M. and Vince, James E. (2017) Active MLKL triggers the NLRP3 inflammasome in a cell intrinsic manner. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 114 6: E961-E969. doi:10.1073/pnas.1613305114


Author Conos, Stephanie A.
Chen, Kaiwen W.
De Nardo, Dominic
Hara, Hideki
Whitehead, Lachlan
Núñez, Gabriel
Masters, Seth L.
Murphy, James M.
Schroder, Kate
Vaux, David L.
Lawlor, Kate E.
Lindqvist, Lisa M.
Vince, James E.
Title Active MLKL triggers the NLRP3 inflammasome in a cell intrinsic manner
Journal name Proceedings of the National Academy of Sciences of the United States of America (PNAS)   Check publisher's open access policy
ISSN 1091-6490
Publication date 2017-01-16
Year available 2017
Sub-type Article (original research)
DOI 10.1073/pnas.1613305114
Open Access Status Not yet assessed
Volume 114
Issue 6
Start page E961
End page E969
Total pages 9
Place of publication Washington, DC United States
Publisher National Academy of Sciences
Language eng
Abstract Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)- like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKLinduced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKLdependent diseases.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01AI063331
1051210
DP160102702
9000220
1052598
1035502
1020136
1105754
461221
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 23 Jan 2017, 13:58:06 EST by Dr Kate Schroder on behalf of School of Chemistry & Molecular Biosciences