MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis

Andre L. Samson (), Ying Zhang, Niall D. Geoghegan, Xavier J. Gavin, Katherine A. Davies, Michael J. Mlodzianoski, Lachlan W. Whitehead, Daniel Frank, Sarah E. Garnish, Cheree Fitzgibbon, Anne Hempel, Samuel N. Young, Annette V. Jacobsen, Wayne Cawthorne, Emma J. Petrie, Maree C. Faux, Kristy Shield-Artin, Najoua Lalaoui, Joanne M. Hildebrand, John Silke, Kelly L. Rogers, Guillaume Lessene, Edwin D. Hawkins () and James M. Murphy ()
Additional contact information
Andre L. Samson: The Walter and Eliza Hall Institute of Medical Research
Ying Zhang: The Walter and Eliza Hall Institute of Medical Research
Niall D. Geoghegan: The Walter and Eliza Hall Institute of Medical Research
Xavier J. Gavin: The Walter and Eliza Hall Institute of Medical Research
Katherine A. Davies: The Walter and Eliza Hall Institute of Medical Research
Michael J. Mlodzianoski: The Walter and Eliza Hall Institute of Medical Research
Lachlan W. Whitehead: The Walter and Eliza Hall Institute of Medical Research
Daniel Frank: The Walter and Eliza Hall Institute of Medical Research
Sarah E. Garnish: The Walter and Eliza Hall Institute of Medical Research
Cheree Fitzgibbon: The Walter and Eliza Hall Institute of Medical Research
Anne Hempel: The Walter and Eliza Hall Institute of Medical Research
Samuel N. Young: The Walter and Eliza Hall Institute of Medical Research
Annette V. Jacobsen: The Walter and Eliza Hall Institute of Medical Research
Wayne Cawthorne: The Walter and Eliza Hall Institute of Medical Research
Emma J. Petrie: The Walter and Eliza Hall Institute of Medical Research
Maree C. Faux: The Walter and Eliza Hall Institute of Medical Research
Kristy Shield-Artin: The Walter and Eliza Hall Institute of Medical Research
Najoua Lalaoui: The Walter and Eliza Hall Institute of Medical Research
Joanne M. Hildebrand: The Walter and Eliza Hall Institute of Medical Research
John Silke: The Walter and Eliza Hall Institute of Medical Research
Kelly L. Rogers: The Walter and Eliza Hall Institute of Medical Research
Guillaume Lessene: The Walter and Eliza Hall Institute of Medical Research
Edwin D. Hawkins: The Walter and Eliza Hall Institute of Medical Research
James M. Murphy: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. RIPK3-mediated phosphorylation is thought to initiate MLKL oligomerization, membrane translocation and membrane disruption, although the precise choreography of events is incompletely understood. Here, we use single-cell imaging approaches to map the chronology of endogenous human MLKL activation during necroptosis. During the effector phase of necroptosis, we observe that phosphorylated MLKL assembles into higher order species on presumed cytoplasmic necrosomes. Subsequently, MLKL co-traffics with tight junction proteins to the cell periphery via Golgi-microtubule-actin-dependent mechanisms. MLKL and tight junction proteins then steadily co-accumulate at the plasma membrane as heterogeneous micron-sized hotspots. Our studies identify MLKL trafficking and plasma membrane accumulation as crucial necroptosis checkpoints. Furthermore, the accumulation of phosphorylated MLKL at intercellular junctions accelerates necroptosis between neighbouring cells, which may be relevant to inflammatory bowel disease and other necroptosis-mediated enteropathies.

Date: 2020
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DOI: 10.1038/s41467-020-16887-1

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