2. Academic Validation
  3. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

  • Nat Cell Biol. 2014 Jan;16(1):55-65. doi: 10.1038/ncb2883.
Zhenyu Cai 1,  Siriporn Jitkaew 1,  Jie Zhao 1,  Hsueh-Cheng Chiang 2,  Swati Choksi 3,  Jie Liu 4,  Yvona Ward 3,  Ling-Gang Wu 2,  Zheng-Gang Liu 3
Affiliations

Affiliations

  • 1 1] Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
  • 2 Synaptic Transmission Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 3 Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 4 Center for Molecular Medicine, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
PMID: 24316671 DOI: 10.1038/ncb2883
Abstract

The Mixed Lineage Kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced Necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced Necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced Necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating Necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced Necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca(2+) influx and TNF-induced Necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced Necroptosis.

Figures