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Cell Rep. 2014 May 22;7(4):971-81. doi: 10.1016/j.celrep.2014.04.026. Epub 2014 May 9.

MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates.

Author information

1
VIB Inflammation Research Center, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.
2
Department of Cell Biology, University of Geneva, 1211 Geneva 4, Switzerland.
3
Microscopy Core Facility, VIB Inflammation Research Center, VIB/Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium.
4
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
5
Unit for Structural Biology and Biophysics, Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University, K.L. Ledeganckstraat 35, 9000 Ghent, Belgium.
6
VIB Inflammation Research Center, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium; Methusalem Program, Ghent University, Technologiepark 927, 9052 Zwijnaarde-Ghent, Belgium. Electronic address: peter.vandenabeele@irc.vib-ugent.be.

Abstract

Although mixed lineage kinase domain-like (MLKL) protein has emerged as a specific and crucial protein for necroptosis induction, how MLKL transduces the death signal remains poorly understood. Here, we demonstrate that the full four-helical bundle domain (4HBD) in the N-terminal region of MLKL is required and sufficient to induce its oligomerization and trigger cell death. Moreover, we found that a patch of positively charged amino acids on the surface of the 4HBD binds to phosphatidylinositol phosphates (PIPs) and allows recruitment of MLKL to the plasma membrane. Importantly, we found that recombinant MLKL, but not a mutant lacking these positive charges, induces leakage of PIP-containing liposomes as potently as BAX, supporting a model in which MLKL induces necroptosis by directly permeabilizing the plasma membrane. Accordingly, we found that inhibiting the formation of PI(5)P and PI(4,5)P2 specifically inhibits tumor necrosis factor (TNF)-mediated necroptosis but not apoptosis.

PMID:
24813885
DOI:
10.1016/j.celrep.2014.04.026
[Indexed for MEDLINE]
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