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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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

Andre L Samson1,2, Ying Zhang3,4, Niall D Geoghegan3,4

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. samson.a@wehi.edu.au.

Nature Communications
|June 21, 2020
PubMed

Insights

Mixed lineage kinase domain-like (MLKL) activation initiates necroptosis. Phosphorylated MLKL travels to the cell membrane, forming hotspots that accelerate cell death and may impact inflammatory diseases.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Immunology

Background:

  • Necroptosis is a programmed inflammatory cell death pathway.
  • Mixed lineage kinase domain-like (MLKL) protein is essential for necroptosis execution.
  • The spatiotemporal regulation of MLKL during necroptosis is not fully understood.

Purpose of the Study:

  • To elucidate the chronological events of endogenous human MLKL activation during necroptosis.
  • To identify key checkpoints in the MLKL-mediated necroptotic pathway.
  • To investigate the role of MLKL trafficking in intercellular necroptosis propagation.

Main Methods:

  • Single-cell imaging techniques to track endogenous MLKL.
  • Analysis of MLKL localization and assembly during necroptosis.
  • Investigating the involvement of cellular transport machinery (Golgi, microtubules, actin).

Main Results:

  • Phosphorylated MLKL forms higher-order structures at cytoplasmic necrosomes.
  • MLKL traffics with tight junction proteins to the cell periphery via Golgi-microtubule-actin pathways.
  • MLKL and tight junction proteins accumulate at the plasma membrane as hotspots, accelerating necroptosis between cells.

Conclusions:

  • MLKL trafficking and plasma membrane accumulation are critical checkpoints in necroptosis.
  • Intercellular accumulation of MLKL at junctions enhances necroptosis spread.
  • Findings may be relevant to necroptosis-associated enteropathies like inflammatory bowel disease.

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