MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates
MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates
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DOI：
10.1016/j.celrep.2014.04.026
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发表时间：
2014-05-01
期刊：
影响因子：
8.8
通讯作者：
Vandenabeele, Peter
中科院分区：
文献类型：
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作者：
Dondelinger, Yves;Declercq, Wim;Vandenabeele, Peter
虽然混合谱系激酶结构域样（MLKL）蛋白已成为一个特定的和关键的蛋白质坏死诱导，MLKL如何转导死亡信号仍然知之甚少。在这里，我们证明，在MLKL的N-末端区域的完整的四螺旋束域（4 HBD）是必需的，足以诱导其寡聚化和触发细胞死亡。此外，我们发现4 HBD表面上的一片带正电荷的氨基酸与磷脂酰肌醇磷酸（PIP）结合，并允许MLKL募集到质膜。重要的是，我们发现重组MLKL，而不是缺乏这些正电荷的突变体，诱导含有PIP的脂质体的泄漏与BAX一样有效，支持MLKL通过直接透化质膜诱导坏死性凋亡的模型。因此，我们发现抑制PI（5）P和PI（4，5）P-2的形成特异性抑制肿瘤坏死因子（TNF）介导的坏死性凋亡，但不抑制凋亡。
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.