MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates.

By Y. Dondelinger, W. Declercq, S. Montessuit, R. Roelandt, A. Gonçalves, I. Bruggeman, Paco Hulpiau, K. Weber, C. Sehon, R. Marquis and 6 more. Cell Reports, 2014

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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.

Subfields: Infectious Diseases, Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/2f7304b981b62db4923bc9bb40aa4a6384462793

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Citations in the corpus

GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death (2016, neutral): “Binding of the FHBD to negatively charged phosphatidylinositol phosphates has been proposed to recruit MLKL to the plasma membrane allowing it to directly permeabilize the membrane by forming a pore (Dondelinger et al , 2014; Su et al , 2014; Wang et al , 2014).”
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 (2014, background): “specific phospholipids, resulting in the loss of barrier function.(170,171,174,175,188) Recent data argue against an essential role for mitochondria in necroptosis.”
Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions (2022, background): “Within the complex formed by this association, mixed lineage kinase domain-like is further activated by RIPK3, which eventually leads to cell death.(205) Concurrently, a cascade of inflammatory reactions, including secretion of proinflammatory cytokines, favors necrosis damage and exacerbates ischem”
Necroptosis: Mechanisms and Relevance to Disease (2016, neutral): “At the membrane, the NB domain of MLKL undergoes a rolling-over process to expose high-affinity binding sites for PIP species (phosphatidylinositol 4,5-bisphosphate being the preferred interaction partner), which results in the displacement of the brace domain and binding stabilization (20, 21).”