Related Experiment Video

Updated: Dec 21, 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

Targeting RIPK3 oligomerization blocks necroptosis without inducing apoptosis

Wenjuan Li1,2, Hengxiao Ni1,2, Shaofeng Wu1,2,3

  • 1School of Life Sciences, Xiamen University, Xiamen, China.

FEBS Letters
|May 16, 2020
PubMed

Insights

Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) inhibition can treat diseases, but may cause apoptosis. PP2, a RIPK3 inhibitor, blocks necroptosis without inducing apoptosis by disrupting RIPK3 oligomerization.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Drug discovery

Background:

  • Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is crucial in necroptosis, a programmed cell death pathway implicated in diseases like Crohn's disease.
  • Targeting RIPK3 kinase activity is a therapeutic strategy, but can paradoxically trigger apoptosis.
  • Developing safe and effective RIPK3 inhibitors is essential for treating necroptosis-associated pathologies.

Discussion:

  • PP2, a SRC inhibitor, effectively inhibits TNF-α-induced necroptosis without inducing apoptosis.
  • PP2 functions as a dual inhibitor of SRC and RIPK3.
  • PP2 disrupts RIPK3 oligomerization, a key step in necroptosis signaling, without affecting RIPK1-RIPK3-MLKL complex integrity or RIPK3 autophosphorylation.

Key Insights:

  • RIPK3 oligomerization is essential for downstream MLKL phosphorylation and activation during necroptosis.
  • PP2's mechanism involves inhibiting RIPK3 oligomerization rather than its kinase activity.
  • This study reveals a novel therapeutic strategy targeting RIPK3 oligomerization.

Outlook:

  • Targeting RIPK3 oligomerization offers a promising therapeutic avenue for necroptosis-associated diseases.
  • Further research into PP2 and similar compounds could lead to new treatments with improved safety profiles.
  • Understanding RIPK3 oligomerization dynamics is critical for advancing necroptosis-targeted therapies.
Keywords:
RIPK3apoptosisnecroptosisoligomerizationphosphorylation

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