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Cited by 485Inflammasome and immune disordersCell death mechanisms and regulationImmune Response and Inflammation

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

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Conos, Stephanie A., Chen, Kaiwen W., De Nardo, Dominic, Hara, Hideki, Whitehead, Lachlan, Núñez, Gabriel, Masters, Seth L., Murphy, James M. +5 more·2017·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1613305114PMC PMC5307433
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Abstract

Significance: 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.

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Crossref · 10.1073/pnas.1613305114

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  • Multiple components of molecular machinery for necroptosis-including ZBP1, RIPK3, MLKL, and TNFR1 (mainly via NF-κB)-impinge on control of inflammasome, a supramolecular platform for activation of CASP1 and consequent secretion of mature IL1B and IL18.

    “Importantly, multiple components of the molecular machinery for necroptosis—including ZBP1, RIPK3, MLKL, and TNFR1 (mainly via NF-κB)—impinge on the control of the so-called “inflammasome”, a supramolecular platform for the activation of CASP1 and consequent secretion of mature interleukin 1 beta (IL1B; best known as IL-1β) and IL18 [524–529].”

    From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [524]

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Research works printed but not linked: 34

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Authors
Conos, S. A., Chen, K. W., De Nardo, D., Hara, H., Whitehead, L., Núñez, G., Masters, S. L., Murphy, J. M., Schroder, K., Vaux, D. L., Lawlor, K. E., Lindqvist, L. M., & Vince, J. E.
Affiliations
  • The University of Melbourne (AU)
  • The University of Queensland (AU)
  • Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia;
  • University of Michigan (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-01-17
Volume
114
Issue
6
Pages
E961-E969
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1613305114
PMC
PMC5307433
OpenAlex
W2572113648
Cited by
485
References
8
Citations by year
2026: 41 · 2025: 51 · 2024: 61 · 2023: 67 · 2022: 74 · 2021: 50 · 2020: 45 · 2019: 37 · 2018: 43 · 2017: 16
FWCI
15.74
Type
journal article
Language
en
Update notices
correction (2017-07-03)
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 181 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Funders
  • HHS | National Institutes of Health (R01AI063331, R01DK091191)
  • Department of Health, Australian Government | National Health and Medical Research Council (1051210, 1101405, 1057905, 1052598, 1035502, 1020136, 1105754, 461221)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
MLKL, NLRP3 inflammasome, necroptosis, RIPK3, IL-1β secretion, caspase-1, ASC specks, intracellular potassium, membrane association, NF-κB activation, pyroptosis, gasdermin D, inflammation
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Bone Marrow Cells, Humans, Lipopolysaccharides, Macrophages, Necrosis, Protein Kinases, Apoptosis, Mice, Knockout, Caspase 1, Cell Line, Tumor, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Interleukin-1beta, Protein Multimerization, Inflammasomes

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