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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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Activated MLKL attenuates autophagy following its translocation to intracellular membranes

Daniel Frank1,2, David L Vaux1,2, James M Murphy1,2

  • 1Cell Signalling and Cell Death Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia.

Journal of Cell Science
|February 3, 2019
PubMed

Insights

Necroptosis, a programmed cell death pathway, involves the protein MLKL. This study reveals MLKL inhibits autophagy during necroptosis, impacting autophagic flux and cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Necroptosis is an inflammatory programmed cell death pathway.
  • It is regulated by mixed-lineage kinase domain-like protein (MLKL) and receptor-interacting protein kinase-3 (RIPK3).
  • MLKL activation leads to plasma membrane disruption and cell lysis.

Purpose of the Study:

  • To investigate the relationship between necroptosis and autophagy.
  • To determine the role of MLKL in modulating autophagic processes during necroptosis.

Main Methods:

  • Activation of necroptosis in mouse dermal fibroblasts (MDFs) and HT-29 human colorectal cancer cells.
  • Monitoring of autophagic markers, specifically lipidated LC3B (MAP1LC3B).
  • Assessing autophagic flux and autophagosome/autolysosome function.

Main Results:

  • Necroptosis activation led to an MLKL-dependent accumulation of lipidated LC3B.
  • This accumulation resulted from the inhibition of autophagic flux, not autophagy activation.
  • MLKL-mediated autophagy inhibition required its association with intracellular membranes.
  • A decrease in autophagosome and/or autolysosome function was observed.

Conclusions:

  • MLKL plays a novel role in inhibiting autophagy during necroptosis.
  • This inhibition impacts autophagic flux and contributes to the overall necroptotic process.
  • Understanding this interplay is crucial for targeting necroptosis in diseases like cancer.
Keywords:
AutophagyLC3MLKLNecroptosis

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