MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D

Necroptosis is a form of programmed cell death defined by activation of the kinase receptor interacting protein kinase 3 and its downstream effector, the pseudokinase mixed lineage kinase domain-like (MLKL). Activated MLKL translocates to the cell membrane and disrupts it, leading to loss of cellula...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2017-03, Vol.198 (5), p.2156-2164
Main Authors: Gutierrez, Kimberley D, Davis, Michael A, Daniels, Brian P, Olsen, Tayla M, Ralli-Jain, Pooja, Tait, Stephen W G, Gale, Jr, Michael, Oberst, Andrew
Format: Article
Language:English
Subjects:
Activation
Apoptosis
Cell activation
Cell death
Cell Line
Cell Membrane - metabolism
Concurrent processing
Homeostasis
Humans
IL-1β
Inflammasomes
Inflammasomes - metabolism
Interleukin-1beta - metabolism
Kinases
MAP kinase
Monocytes - physiology
Necroptosis
Necrosis
Neoplasm Proteins - metabolism
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Potassium
Potassium - metabolism
Protein kinase
Protein Kinases - metabolism
Signal Transduction
Tumor Necrosis Factor-alpha - metabolism
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Summary:Necroptosis is a form of programmed cell death defined by activation of the kinase receptor interacting protein kinase 3 and its downstream effector, the pseudokinase mixed lineage kinase domain-like (MLKL). Activated MLKL translocates to the cell membrane and disrupts it, leading to loss of cellular ion homeostasis. In this study, we use a system in which this event can be specifically triggered by a small-molecule ligand to show that MLKL activation is sufficient to induce the processing and release of bioactive IL-1β. MLKL activation triggers potassium efflux and assembly of the NLRP3 inflammasome, which is required for the processing and activity of IL-1β released during necroptosis. Notably, MLKL activation also causes cell membrane disruption, which allows efficient release of IL-1β independently of the recently described pyroptotic effector gasdermin-D. Taken together, our findings indicate that MLKL is an endogenous activator of the NLRP3 inflammasome, and that MLKL activation provides a mechanism for concurrent processing and release of IL-1β independently of gasdermin-D.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1601757