2. Academic Validation
  3. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3

Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3

  • Mol Cell. 2014 Apr 10;54(1):133-146. doi: 10.1016/j.molcel.2014.03.003.
Huayi Wang 1,  Liming Sun 1,  Lijing Su 2,  Josep Rizo 2,  Lei Liu 1,  Li-Feng Wang 3,  Fu-Sheng Wang 3,  Xiaodong Wang 4
Affiliations

Affiliations

  • 1 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
  • 2 Departments of Biophysics, Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
  • 3 Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing 100039, China.
  • 4 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China. Electronic address: [email protected].
PMID: 24703947 DOI: 10.1016/j.molcel.2014.03.003
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.

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