Molecular Cell
Volume 54, Issue 1, 10 April 2014, Pages 133-146
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Article
Mixed Lineage Kinase Domain-like Protein MLKL Causes Necrotic Membrane Disruption upon Phosphorylation by RIP3

https://doi.org/10.1016/j.molcel.2014.03.003Get rights and content
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Highlights

  • Phosphorylation of MLKL at T357/S358 by RIP3 kinase drives its oligomerization

  • MLKL oligomer translocates from cytosol to intracellular and plasma membranes

  • MLKL oligomer directly disrupts membrane integrity during necroptosis

  • The MLKL phosphorylation occurs during drug-induced liver injury in human

Summary

Programmed necrotic cell death induced by the tumor necrosis factor alpha (TNF-α) family of cytokines is dependent on a kinase cascade consisting of receptor-interacting kinases RIP1 and RIP3. How these kinase activities cause cells to die by necrosis is not known. The mixed lineage kinase domain-like protein MLKL is a functional RIP3 substrate that binds to RIP3 through its kinase-like domain but lacks kinase activity of its own. RIP3 phosphorylates MLKL at the T357 and S358 sites. Reported here is the development of a monoclonal antibody that specifically recognizes phosphorylated MLKL in cells dying of this pathway and in human liver biopsy samples from patients suffering from drug-induced liver injury. The phosphorylated MLKL forms an oligomer that binds to phosphatidylinositol lipids and cardiolipin. This property allows MLKL to move from the cytosol to the plasma and intracellular membranes, where it directly disrupts membrane integrity, resulting in necrotic death.

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