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The role of the kinases RIP1 and RIP3 in TNF-induced necrosis

Peter Vandenabeele1, Wim Declercq, Franky Van Herreweghe

  • 1Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, 9052 Zwijnaarde, Belgium. Peter.Vandenabeele@dmbr.UGent.be

Science Signaling
|April 1, 2010
PubMed

Insights

Tumor necrosis factor (TNF) signaling triggers cell death pathways like apoptosis and necrosis. Key kinases RIP1 and RIP3 regulate necrosis via the necrosome, impacting cell energy and ROS production.

Area of Science:

  • Cellular biology
  • Immunology
  • Biochemistry

Background:

  • Tumor necrosis factor (TNF) is a critical mediator of cellular stress, inflammation, and immunity.
  • TNF signaling orchestrates diverse cellular outcomes including gene induction, apoptosis, and necrosis.
  • Receptor-interacting protein 1 (RIP1) and RIP3 kinases are central regulators of TNF-induced necrosis.

Purpose of the Study:

  • To elucidate the signaling mechanisms underlying TNF-induced necrosis.
  • To investigate the role of RIP1 and RIP3 in necrosome formation and function.
  • To explore the link between cellular bioenergetics, reactive oxygen species (ROS), and necrosis.

Main Methods:

  • Analysis of TNF signaling complexes and their downstream effects.
  • Investigating the activation and regulation of RIP1 and RIP3 kinases.
  • Studying the role of the necrosome in regulating metabolic pathways and ROS production.

Main Results:

  • TNF stimulation leads to distinct signaling complexes dictating cell fate (survival, apoptosis, necrosis).
  • RIP1 and RIP3 kinases are essential for necrosome formation, activating metabolic enzymes and promoting ROS generation.
  • The necrosome links cellular bioenergetics to cytotoxicity, involving mitochondrial complex I and NADPH oxidases.

Conclusions:

  • RIP1 and RIP3 are key regulators of TNF-induced necrosis, linking signaling to metabolic reprogramming and ROS production.
  • Understanding these pathways offers therapeutic targets for diseases involving cell loss and cancer immunogenic cell death.

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