Related Experiment Video

Updated: Jul 5, 2025

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

10.9K

LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL

Nadine Weinelt1, Kaja Nicole Wächtershäuser2, Gulustan Celik1

  • 1Institute for Experimental Paediatric Haematology and Oncology (EPHO), Goethe University Frankfurt, Komturstrasse 3a, 60528, Frankfurt am Main, Germany.

Cell Death & Disease
|January 20, 2024
PubMed

Insights

Linear ubiquitin chain assembly complex (LUBAC) regulates necroptosis by controlling mixed lineage kinase domain-like (MLKL) membrane accumulation in human cells. This finding identifies LUBAC as a novel necroptosis checkpoint, crucial for inflammatory cell death.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Phosphorylated mixed lineage kinase domain-like (MLKL) accumulation at the plasma membrane triggers necroptosis, a form of inflammatory cell death.
  • Endo- and exocytosis are known to limit MLKL membrane accumulation, but their precise roles in necroptosis regulation are not fully understood.

Purpose of the Study:

  • To identify novel regulatory checkpoints controlling MLKL membrane accumulation and necroptosis.
  • To investigate the role of the linear ubiquitin chain assembly complex (LUBAC) in necroptosis.

Main Methods:

  • Utilized human cell lines and primary human pancreatic organoids.
  • Investigated the impact of LUBAC activity on tumor necrosis factor α (TNFα)-mediated necroptosis.
  • Analyzed MLKL phosphorylation and membrane accumulation.

Main Results:

  • Identified LUBAC-mediated M1 poly-ubiquitination as a novel necroptosis regulatory checkpoint downstream of activated MLKL.
  • Loss of LUBAC activity inhibited TNFα-induced necroptosis by preventing MLKL membrane accumulation, without affecting upstream signaling.
  • Confirmed LUBAC-dependent necroptosis activation in primary human pancreatic organoids.

Conclusions:

  • LUBAC acts as a novel regulator of necroptosis by promoting MLKL membrane accumulation in human cells.
  • LUBAC is essential for TNFα-mediated necroptosis in human cells.
  • Primary human organoids provide a near-physiological model for studying necroptosis.

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