Mixed Lineage Kinase Domain-like Protein MLKL Causes Necrotic Membrane Disruption upon Phosphorylation by RIP3

Huayi Wang, Liming Sun, Lijing Su, Jose Rizo-Rey, Lei Liu, Li Feng Wang, Fu Sheng Wang, Xiaodong Wang

Research output: Contribution to journalArticle

613 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)133-146
Number of pages14
JournalMolecular cell
Volume54
Issue number1
DOIs
StatePublished - Apr 10 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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