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MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates

Yves Dondelinger UGent, Wim Declercq UGent, Sylvie Montessuit, Ria Roelandt UGent, Amanda Gonçalves UGent, Inge Bruggeman UGent, Paco Hulpiau UGent, Kathrin Weber, Clark A Sehon, Robert W Marquis, et al. (2014) CELL REPORTS. 7(4). p.971-981
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
DEPENDENT APOPTOSIS, TNF-ALPHA, NECROPTOSIS, RIP3, DEPLETION, PROGRAMMED NECROSIS, NECROTIC CELL-DEATH, PLECKSTRIN HOMOLOGY DOMAINS, DOMAIN-LIKE PROTEIN, MIXED LINEAGE KINASE
journal title
CELL REPORTS
Cell Reports
volume
7
issue
4
pages
971 - 981
Web of Science type
Article
Web of Science id
000336495700007
JCR category
CELL BIOLOGY
JCR impact factor
8.358 (2014)
JCR rank
27/184 (2014)
JCR quartile
1 (2014)
ISSN
2211-1247
DOI
10.1016/j.celrep.2014.04.026
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
5658575
handle
http://hdl.handle.net/1854/LU-5658575
date created
2014-07-15 15:42:47
date last changed
2017-07-24 13:50:27
@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},
  keyword      = {DEPENDENT APOPTOSIS,TNF-ALPHA,NECROPTOSIS,RIP3,DEPLETION,PROGRAMMED NECROSIS,NECROTIC CELL-DEATH,PLECKSTRIN HOMOLOGY DOMAINS,DOMAIN-LIKE PROTEIN,MIXED LINEAGE KINASE},
  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},
}

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.