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

Samson, AL; Zhang, Y; Geoghegan, ND; Gavin, XJ; Davies, KA; Mlodzianoski, MJ; Whitehead, LW; Frank, D; Garnish, SE; Fitzgibbon, C; Hempel, A; Young, SN; Jacobsen, AV; Cawthorne, W; Petrie, EJ; Faux, MC; Shield-Artin, K; Lalaoui, N; Hildebrand, JM; Silke, J; Rogers, KL; Lessene, G; Hawkins, ED; Murphy, JM

Author(s): Samson, AL; Zhang, Y; Geoghegan, ND; Gavin, XJ; Davies, KA; Mlodzianoski, MJ; Whitehead, LW; Frank, D; Garnish, SE; Fitzgibbon, C; Hempel, A; Young, SN; Jacobsen, AV; Cawthorne, W; Petrie, EJ; Faux, MC; Shield-Artin, K; Lalaoui, N; Hildebrand, JM; Silke, J; Rogers, KL; Lessene, G; Hawkins, ED; Murphy, JM;
Details: Publication Year 2020-06-19,Volume 11,Issue #1,Page 3151
Journal Title: Nature Communications
Publication Type: Journal Article
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.
Publisher: NPG
Research Division(s): Inflammation; Chemical Biology; Advanced Technology And Biology; Structural Biology; Personalised Oncology; Cancer Biology And Stem Cells
PubMed ID: 32561730
Link To PubMed Central Version: https://doi.org/10.1038/s41467-020-16887-1
Publisher's Version: https://doi.org/10.1038/s41467-020-16887-1
NHMRC Grants: NHMRC/1142669, NHMRC/1117089, NHMRC/1159488, NHMRC/1105754, NHMRC/1124735, NHMRC/1124737, NHMRC/1105023,
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Creation Date: 2020-06-22 11:52:56

Last Modified: 2021-02-01 11:54:56