MLKL activation triggers NLRP3-mediated processing and release of il-1β independently of gasdermin-d

Kimberley D. Gutierrez, Michael A. Davis, Brian P. Daniels, Tayla M. Olsen, Pooja Ralli-Jain, Stephen W.G. Tait, Michael Gale, Andrew Oberst

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


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 thatMLKLactivation 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.

Original languageEnglish (US)
Pages (from-to)2156-2164
Number of pages9
JournalJournal of Immunology
Issue number5
StatePublished - Mar 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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