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Updated: Feb 4, 2026

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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Nuclear RIPK3 and MLKL contribute to cytosolic necrosome formation and necroptosis

Kathrin Weber1,2, Ria Roelandt3,4, Inge Bruggeman3,4

  • 1VIB Inflammation Research Center, Technologiepark 927, 9052, Zwijnaarde-Ghent, Belgium. k.w.e@gmx.de.

Communications Biology
|October 2, 2018
PubMed

Insights

Necroptotic signaling proteins RIPK1, RIPK3, and MLKL shuttle between the nucleus and cytoplasm. Nuclear events regulate the formation of the necrosome complex, controlling programmed cell death.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Necroptosis is a regulated form of necrosis crucial for immunity and development.
  • The necrosome, a cytosolic complex of RIPK1, RIPK3, and MLKL, mediates necroptosis.
  • The precise regulation of necrosome formation remains incompletely understood.

Purpose of the Study:

  • To investigate the subcellular localization and nuclear-cytosolic transport of key necroptosis signaling components.
  • To determine the role of nuclear events in the regulation of necrosome assembly and necroptotic cell death.

Main Methods:

  • Immunofluorescence microscopy to track protein localization.
  • Biochemical assays to detect protein modifications like ubiquitination and phosphorylation.
  • Pharmacological inhibition of nuclear export pathways.
  • Cell viability assays to quantify necroptosis.

Main Results:

  • RIPK3 and MLKL exhibit dynamic nucleocytosolic shuttling, while RIPK1 is constitutively present in both compartments.
  • TNF-induced necroptosis triggers RIPK1 ubiquitination and subsequent MLKL phosphorylation and oligomerization within the nucleus.
  • Inhibition of nuclear export retains RIPK3 and MLKL in the nucleus, impairs cytosolic necrosome formation, and reduces cell death.

Conclusions:

  • Nuclear translocation and processing of necroptotic signaling molecules are critical for regulating necrosome assembly.
  • The passage of RIPK1, RIPK3, and MLKL through the nucleus serves as a regulatory checkpoint for necroptotic cell death.
  • Targeting nuclear export may offer a therapeutic strategy to control necroptosis.

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