Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-16887-1
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Funding
- Australian National Health and Medical Research Council [1142669, 1117089, 1159488, 1105754, 1172929, 1124735, 1124737, 1105023, IRIISS 9000587]
- Victorian Cancer Agency [17030]
- CASS Foundation
- Australian Cancer Research Foundation
- Victorian Government Operational Infrastructure Support scheme
- Australian Research Training Program Scholarship
- Melbourne Research Scholarship
- AINSE postgraduate research award
- National Health and Medical Research Council of Australia [1105023, 1117089, 1124737, 1142669, 1159488] Funding Source: NHMRC
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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. Mixed lineage kinase domain-like (MLKL) is the terminal protein in the pro-inflammatory necroptotic cell death program. Here the authors show that MLKL trafficking and plasma membrane accumulation are crucial necroptosis checkpoints, and that accumulation of phosphorylated MLKL at intercellular junctions promotes necroptosis.
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