Dondelinger Y Declercq W Montessuit S Roelandt R Goncalves A Bruggeman I Hulpiau P Weber K Sehon CA Marquis RW Bertin J Gough PJ Savvides S Martinou JC Bertrand MJ Vandenabeele P 2014 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. https://sonar.ch/global/documents/206050 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2014.04.026 info:eu-repo/semantics/altIdentifier/pmid/24813885 Cell reports. - 2014 Cell Death Cell Line Cell Membrane HEK293 Cells Humans Liposomes Necrosis Phosphatidylinositol Phosphates Phosphorylation Protein Kinases Recombinant Proteins Signal Transduction Tumor Necrosis Factor-alpha MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. http://purl.org/coar/resource_type/c_6501