MLKL activation triggers NLRP3-mediated processing and release of IL-1β independently of gasdermin-D

Gutierrez, K. D., Davis, M. A., Daniels, B. P., Olsen, T. M., Ralli-Jain, P., Tait, S. W.G. , Gale, Jr., M. and Oberst, A. (2017) MLKL activation triggers NLRP3-mediated processing and release of IL-1β independently of gasdermin-D. Journal of Immunology, 198(5), pp. 2156-2164. (doi:10.4049/jimmunol.1601757) (PMID:28130493) (PMCID:PMC5321867)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tait, Professor Stephen
Authors: Gutierrez, K. D., Davis, M. A., Daniels, B. P., Olsen, T. M., Ralli-Jain, P., Tait, S. W.G., Gale, Jr., M., and Oberst, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Immunology
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606
Published Online:21 February 2017

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