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Updated: Dec 28, 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

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TRADD Mediates RIPK1-Independent Necroptosis Induced by Tumor Necrosis Factor

Lili Wang1, Xixi Chang1, Jinli Feng2

  • 1Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing, China.

Frontiers in Cell and Developmental Biology
|February 11, 2020
PubMed

Insights

Tumor necrosis factor (TNF) can trigger programmed cell death called necroptosis. This study identifies TRADD as a key protein that initiates necroptosis independently of RIPK1, revealing a new mechanism for cell death.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Necroptosis is a programmed cell death pathway initiated by proteins like RIPK1, RIPK3, and MLKL.
  • The role of RIPK1 in TNF-induced necroptosis is complex, with genetic elimination sometimes enhancing the process.
  • Mechanisms of RIPK1-independent necroptosis, particularly involving RIPK3, remain unclear.

Purpose of the Study:

  • To investigate the role of TRADD in TNF-induced necroptosis.
  • To elucidate the mechanism by which TRADD mediates RIPK1-independent necroptosis.
  • To identify new targets for controlling necroptosis.

Main Methods:

  • Utilized RIPK1-knockdown L929 and HT-22 cell lines.
  • Performed mechanistic studies to analyze protein interactions and signaling pathways.
  • Assessed the role of TRADD in RIPK3 phosphorylation and oligomerization.
  • Measured reactive oxygen species (ROS) accumulation.

Main Results:

  • TRADD was found to be essential for TNF-induced necroptosis in RIPK1-knockdown cells.
  • TRADD binds to RIPK3, promoting its phosphorylation and oligomerization, thereby activating the RIPK3-MLKL pathway.
  • TRADD is critical for ROS accumulation, contributing to RIPK1-independent necroptosis.
  • TRADD acts as a RIPK3 partner in initiating necroptosis.

Conclusions:

  • TRADD is a novel initiator of TNF-induced necroptosis in a RIPK1-independent manner.
  • TRADD facilitates RIPK3 activation through binding and promoting oligomerization.
  • TRADD-mediated ROS accumulation contributes to this RIPK1-independent necroptosis pathway.
Keywords:
TNF receptor type 1-associated death domain proteinnecroptosisreceptor-interacting serine/threonine-protein kinase 1receptor-interacting serine/threonine-protein kinase 3tumor necrosis factor

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