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

Zhenyu Cai, Siriporn Jitkaew, Jie Zhao, Hsueh Cheng Chiang, Swati Choksi, Jie Liu, Yvona Ward, Ling Gang Wu, Zheng Gang Liu

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472 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)55-65
Number of pages11
JournalNature Cell Biology
Volume16
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

All Science Journal Classification (ASJC) codes

  • Cell Biology

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    Cai, Z., Jitkaew, S., Zhao, J., Chiang, H. C., Choksi, S., Liu, J., Ward, Y., Wu, L. G., & Liu, Z. G. (2014). Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nature Cell Biology, 16(1), 55-65. https://doi.org/10.1038/ncb2883