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Updated: Dec 27, 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

11.2K

PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway

Shiping Hu1, Xixi Chang2, Hongbin Zhu1

  • 1Department of Gastroenterology, The 983rd Hospital of Chinese PLA Joint Logistics Support Force, Tianjin 300142, China.

Cytokine
|March 2, 2020
PubMed

Insights

Phosphatidylinositol-3-kinase (PI3K) is essential for tumor necrosis factor (TNF)-induced necroptosis. PI3K, specifically p110α, interacts with RIP3 to activate the RIP1-RIP3-MLKL pathway, initiating programmed cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Necroptosis is a programmed cell death pathway regulated by RIP1, RIP3, and MLKL.
  • The PI3K-AKT pathway is implicated in TNF-induced necroptosis, but PI3K's specific role remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which PI3K initiates TNF-induced necroptosis.
  • To investigate the role of PI3K, particularly p110α, in the RIP1-RIP3-MLKL signaling cascade.

Main Methods:

  • Chemical inhibition and genetic deletion of PI3K.
  • Knockdown of p110α and use of AKT inhibitors.
  • Analysis of RIP1, RIP3, and MLKL phosphorylation and oligomerization via Western blotting and co-immunoprecipitation.

Main Results:

  • Inhibition or genetic deletion of PI3K blocked TNF-induced necroptosis.
  • p110α knockdown suppressed AKT phosphorylation and RIP1, RIP3, MLKL activation.
  • p110α directly bound to RIP3, facilitating necrosome formation and necroptosis, even without RIP1.

Conclusions:

  • PI3K is a critical initiator of TNF-induced necroptosis.
  • p110α acts as a crucial signaling partner for RIP3 in the RIP1-RIP3-MLKL pathway.
  • PI3K activation is essential for the assembly and function of the necrosome.
Keywords:
NecroptosisPI3KRIP1RIP3TNF

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