2. Academic Validation
  3. MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis

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

  • Nat Commun. 2020 Jun 19;11(1):3151. doi: 10.1038/s41467-020-16887-1.
Andre L Samson 1 2,  Ying Zhang 3 4,  Niall D Geoghegan 3 4,  Xavier J Gavin 3,  Katherine A Davies 3 4,  Michael J Mlodzianoski 3 4,  Lachlan W Whitehead 3 4,  Daniel Frank 3 4,  Sarah E Garnish 3 4,  Cheree Fitzgibbon 3,  Anne Hempel 3,  Samuel N Young 3,  Annette V Jacobsen 3 4,  Wayne Cawthorne 3 4,  Emma J Petrie 3 4,  Maree C Faux 3 4,  Kristy Shield-Artin 3 4,  Najoua Lalaoui 3 4,  Joanne M Hildebrand 3 4,  John Silke 3 4,  Kelly L Rogers 3 4,  Guillaume Lessene 3 4 5,  Edwin D Hawkins 6 7,  James M Murphy 8 9
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 2 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. [email protected].
  • 3 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 4 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • 5 Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, Australia.
  • 6 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 7 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. [email protected].
  • 8 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. [email protected].
  • 9 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. [email protected].
PMID: 32561730 DOI: 10.1038/s41467-020-16887-1
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.

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