title: MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D.
abstract: 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.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Kimberley D
authors.initials: KD
authors.lastname: Gutierrez
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Michael A
authors.identifier: 0000-0002-5406-4128
authors.initials: MA
authors.lastname: Davis
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Daniels
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Tayla M
authors.initials: TM
authors.lastname: Olsen
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Pooja
authors.initials: P
authors.lastname: Ralli-Jain
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom; and.
authors.forename: Stephen W G
authors.identifier: 0000-0001-7697-132X
authors.initials: SW
authors.lastname: Tait
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.|Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109.
authors.forename: Michael
authors.identifier: 0000-0002-6332-7436
authors.initials: M
authors.lastname: Gale
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109; oberst@uw.edu.|Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109.
authors.forename: Andrew
authors.identifier: 0000-0002-9500-7912
authors.initials: A
authors.lastname: Oberst
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D009000:Monocytes / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009336:Necrosis; D009363:Neoplasm Proteins / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D011188:Potassium / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000094524:Gasdermins
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins; D028044:Phosphate-Binding Proteins; D011188:Potassium; D011494:Protein Kinases; D014409:Tumor Necrosis Factor-alpha; C498366:GSDMD protein, human; D000094524:Gasdermins; C570693:MLKL protein, human