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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 compromises plasma membrane integrity by binding to phosphatidylinositol phosphates

Yves Dondelinger1, Wim Declercq1, Sylvie Montessuit2

  • 1VIB Inflammation Research Center, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.

Cell Reports
|May 13, 2014
PubMed

Insights

The N-terminal four-helical bundle domain of mixed lineage kinase domain-like (MLKL) protein is essential for necroptosis. This domain binds to phosphatidylinositol phosphates (PIPs), enabling MLKL to permeabilize the plasma membrane and induce cell death.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mixed lineage kinase domain-like (MLKL) is a key mediator of necroptosis.
  • The precise mechanism by which MLKL signals for cell death is not fully understood.

Purpose of the Study:

  • To elucidate the role of MLKL's N-terminal region in necroptosis.
  • To investigate how MLKL induces cell death at the molecular level.

Main Methods:

  • Investigated the function of MLKL's N-terminal four-helical bundle domain (4HBD).
  • Utilized biochemical assays to assess MLKL oligomerization and liposome permeabilization.
  • Examined the role of positively charged amino acids in MLKL-membrane interactions.
  • Studied the effect of inhibiting phosphatidylinositol phosphate (PIP) synthesis on necroptosis.

Main Results:

  • The MLKL 4HBD is necessary and sufficient for MLKL oligomerization and cell death induction.
  • A positively charged patch on the 4HBD surface binds to PIPs, recruiting MLKL to the plasma membrane.
  • Recombinant MLKL, unlike a charge-mutant, permeabilizes PIP-containing liposomes, similar to BAX.
  • Inhibiting PI(5)P and PI(4,5)P2 formation specifically blocks TNF-mediated necroptosis, not apoptosis.

Conclusions:

  • MLKL directly permeabilizes the plasma membrane to induce necroptosis.
  • PIP binding to MLKL is critical for its recruitment and function in necroptosis.
  • Targeting PIP synthesis may offer specific therapeutic strategies for necroptosis.

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