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

By Zhenyu Cai, Siriporn Jitkaew, Jie Zhao, Hsueh-Cheng Chiang, S. Choksi, Jie Liu, Y. Ward, Ling-Gang Wu, Zheng-Gang Liu. Nature Cell Biology, 2013

1,261 citations recorded by the source corpus.

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 Ca2+ 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 Ca2+ influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.

Subfields: Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/00f08e5c72e69deafe3b9f76348865bcf3b0007a

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Citations in the corpus

MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. (2014, background): “In the first study, the authors report a role of MLKL in regulating extracellular calcium influx from the transient receptor potential melastatin-related 7 (Cai et al., 2014).”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Moreover, it has also been reported that MLKL oligomerization promotes a cascade of intracellular events involving (1) Ca2+ influx, which is presumably mediated by the MLKL target transient receptor potential cation channel subfamily M member 7 (TRPM7) [449]; and (2) PS exposure, which seems to be d”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “Necroptosis is executed by formation of mixed lineage kinase domain-like pseudokinase (MLKL) pores following MLKL phosphorylation downstream of the receptor-interacting protein kinase 1 (RIPK1) and RIPK3 signaling axis [17–21].”
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 (2014, background): “specific phospholipids, resulting in the loss of barrier function.(170,171,174,175,188) Recent data argue against an essential role for mitochondria in necroptosis.”
Regulation of tumour necrosis factor signalling: live or let die (2015, background): “It is suggested that oligomerized MLKL forms pores that are essential for the influx of positively charged ions, such as Na + , K + or Ca 2+ , which is known to be an early event in TNF-induced necrop-tosis 120–122 .”