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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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

Zhenyu Cai1, Siriporn Jitkaew1, Jie Zhao1

  • 11] Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].

Nature Cell Biology
|December 10, 2013
PubMed

Insights

Mixed lineage kinase domain-like protein (MLKL) forms a trimer and moves to the cell membrane during TNF-induced necroptosis. This localization is critical for calcium influx and cell death, identifying TRPM7 as a key downstream target.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Mixed lineage kinase domain-like protein (MLKL) is a critical downstream effector of receptor interacting protein 3 (RIP3) in tumor necrosis factor (TNF)-induced necroptosis.
  • The precise mechanism by which MLKL mediates necroptosis remains incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism of MLKL-mediated TNF-induced necroptosis.
  • To investigate the role of MLKL oligomerization and localization in necroptosis.
  • To identify downstream targets of MLKL involved in calcium influx during necroptosis.

Main Methods:

  • Generation and analysis of MLKL mutants to assess protein localization and function.
  • Investigation of MLKL oligomerization via its amino-terminal coiled-coil domain.
  • Assessment of calcium (Ca2+) influx and its dependence on MLKL localization.
  • Identification of downstream targets of MLKL using molecular biology techniques.

Main Results:

  • MLKL forms a homotrimer through its amino-terminal coiled-coil domain.
  • Trimerized MLKL localizes to the cell plasma membrane during TNF-induced necroptosis.
  • Plasma membrane localization of MLKL is essential for mediating necroptosis and facilitating Ca2+ influx.
  • Transient receptor potential melastatin related 7 (TRPM7) was identified as a downstream target of MLKL essential for Ca2+ influx and necroptosis.

Conclusions:

  • MLKL oligomerization and subsequent plasma membrane recruitment are critical for TNF-induced necroptosis.
  • MLKL-mediated Ca2+ influx, involving TRPM7, is a key event in the necroptosis pathway.
  • This study reveals a novel mechanism for MLKL function in necroptosis, highlighting its role in regulating ion flux.

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