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MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates

(2014) CELL REPORTS. 7(4). p.971-981
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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) P-2 specifically inhibits tumor necrosis factor (TNF)-mediated necroptosis but not apoptosis.
Keywords
DEPENDENT APOPTOSIS, TNF-ALPHA, NECROPTOSIS, RIP3, DEPLETION, PROGRAMMED NECROSIS, NECROTIC CELL-DEATH, PLECKSTRIN HOMOLOGY DOMAINS, DOMAIN-LIKE PROTEIN, MIXED LINEAGE KINASE

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Citation

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Chicago
Dondelinger, Yves, Wim Declercq, Sylvie Montessuit, Ria Roelandt, Amanda Gonçalves, Inge Bruggeman, Paco Hulpiau, et al. 2014. “MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates.” Cell Reports 7 (4): 971–981.
APA
Dondelinger, Y., Declercq, W., Montessuit, S., Roelandt, R., Gonçalves, A., Bruggeman, I., Hulpiau, P., et al. (2014). MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. CELL REPORTS, 7(4), 971–981.
Vancouver
1.
Dondelinger Y, Declercq W, Montessuit S, Roelandt R, Gonçalves A, Bruggeman I, et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. CELL REPORTS. 2014;7(4):971–81.
MLA
Dondelinger, Yves, Wim Declercq, Sylvie Montessuit, et al. “MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates.” CELL REPORTS 7.4 (2014): 971–981. Print.
@article{5658575,
  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) P-2 specifically inhibits tumor necrosis factor (TNF)-mediated necroptosis but not apoptosis.},
  author       = {Dondelinger, Yves and Declercq, Wim and Montessuit, Sylvie and Roelandt, Ria and Gon\c{c}alves, Amanda and Bruggeman, Inge and Hulpiau, Paco and Weber, Kathrin and Sehon, Clark A and Marquis, Robert W and Bertin, John and Gough, Peter J and Savvides, Savvas and Martinou, Jean-Claude and Bertrand, Mathieu and Vandenabeele, Peter},
  issn         = {2211-1247},
  journal      = {CELL REPORTS},
  language     = {eng},
  number       = {4},
  pages        = {971--981},
  title        = {MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates},
  url          = {http://dx.doi.org/10.1016/j.celrep.2014.04.026},
  volume       = {7},
  year         = {2014},
}

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