Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner
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- Stephanie A. Conos
- Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
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- Kaiwen W. Chen
- Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD 4072, Australia;
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- Dominic De Nardo
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia;
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- Hideki Hara
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109;
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- Lachlan Whitehead
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia;
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- Gabriel Núñez
- Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109;
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- Seth L. Masters
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia;
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- James M. Murphy
- Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
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- Kate Schroder
- Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD 4072, Australia;
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- David L. Vaux
- Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
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- Kate E. Lawlor
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia;
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- Lisa M. Lindqvist
- Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;
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- James E. Vince
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia;
抄録
<jats:title>Significance</jats:title> <jats:p>Necroptotic cell death is mediated by activation of the mixed-lineage kinase domain-like protein (MLKL). The inflammation associated with this form of cell death is thought to be due to the release of proinflammatory cellular contents after plasma membrane rupture. In contrast to this prevailing view, we show that MLKL activates the innate immune receptor nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) in a cell-intrinsic manner. Importantly, we show that MLKL-mediated NLRP3 and caspase-1 activation and the secretion of the proinflammatory cytokine IL-1β is a major determinant of necroptotic-derived inflammatory signals. These findings suggest that NLRP3 and IL-1β may be relevant therapeutic targets in MLKL-driven diseases.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 114 (6), E961-, 2017-01-17
Proceedings of the National Academy of Sciences