Related Experiment Video

Updated: Jul 10, 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

NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis

Yves Dondelinger1,2, Dario Priem3,4, Jon Huyghe3,4

  • 1Inflammation Research Center, VIB, Technologiepark 71, 9052, Zwijnaarde-Ghent, Belgium. yves.dondelinger@irc.vib-ugent.be.

Cell Death & Disease
|November 19, 2023
PubMed

Insights

NINJ1 is identified as a key regulator of plasma membrane permeabilization (PMP) and damage-associated molecular pattern (DAMP) release in various necrosis types. Its function is independent of known pore-forming molecules and is triggered by cell swelling.

Area of Science:

  • Cell Biology
  • Immunology
  • Biochemistry

Background:

  • Plasma membrane permeabilization (PMP) is crucial for releasing damage-associated molecular patterns (DAMPs) that initiate sterile inflammation.
  • While MLKL and GSDMs mediate PMP in necroptosis and pyroptosis, the mechanisms in other necrosis forms are poorly understood.

Purpose of the Study:

  • To identify novel regulators of PMP in diverse necrosis pathways.
  • To elucidate the mechanism of PMP and DAMP release beyond known pore-forming proteins.

Main Methods:

  • Investigated NINJ1's role in ferroptosis, parthanatos, H2O2-induced necrosis, and secondary necrosis.
  • Assessed NINJ1's function independently of MLKL, GSDMD, and GSDME.
  • Analyzed NINJ1 activation in relation to lipid peroxidation and reactive oxygen species (ROS).

Main Results:

  • NINJ1 was identified as a critical regulator of PMP and DAMP release across multiple necrosis types.
  • NINJ1's membrane-permeabilizing activity occurs post-metabolic cell death and is independent of MLKL, GSDMD, and GSDME.
  • NINJ1 oligomerization is induced by cell swelling, but a complete activation mechanism remains to be discovered.

Conclusions:

  • NINJ1 is a novel, essential mediator of PMP and DAMP release in various forms of regulated necrosis.
  • NINJ1 acts downstream of ferroptosis triggers and its activation is linked to cell swelling, not solely ROS.
  • Further research is needed to fully uncover the activation pathway of NINJ1-dependent PMP.

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