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RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation.

Maria Feoktistova1, Roman Makarov1, Amir S Yazdi1

  • 1Department of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

International Journal of Molecular Sciences
|November 27, 2021
PubMed
Summary

Receptor-interacting protein kinase 1 (RIPK1) and TNF receptor-associated death domain (TRADD) have distinct roles in TNF signaling. RIPK1 is crucial for apoptosis and necroptosis, while TRADD regulates apoptosis and negatively impacts NIK stabilization.

Keywords:
NF-κBNIKTNF signalingapoptosisnecroptosisripoptosome

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Area of Science:

  • Cellular biology
  • Molecular signaling pathways
  • Immunology

Background:

  • Tumor necrosis factor (TNF) is a key proinflammatory cytokine regulating tissue homeostasis.
  • Receptor-interacting protein kinase 1 (RIPK1) and TNF receptor-associated death domain (TRADD) are central to TNF signal transduction.
  • Their precise roles in controlling cell fate remain debated.

Purpose of the Study:

  • To elucidate the specific functions of RIPK1 and TRADD in TNF signaling.
  • To clarify their contributions to cell death and survival pathways.

Main Methods:

  • Generation of RIPK1- or TRADD-deficient human cell lines.
  • Analysis of TNF-induced apoptosis, necroptosis, and signaling pathway activation (MAPK, NF-κB).
  • Investigation of NIK stabilization and ripoptosome formation.

Main Results:

  • RIPK1 is essential for TNF-induced apoptosis and necroptosis when Inhibitor of Apoptosis Proteins (IAPs) are depleted.
  • TRADD is required for apoptosis but not necroptosis.
  • TRADD acts as a negative regulator of NIK stabilization and ripoptosome formation.
  • RIPK1 prevents TNF-induced ubiquitination and degradation of TRADD.
  • RIPK1 and TRADD are not critical for MAPK activation.

Conclusions:

  • RIPK1 and TRADD exhibit distinct, non-redundant functions in TNF signaling.
  • RIPK1 plays a vital role in mediating TNF-induced cell death pathways.
  • TRADD's function extends to regulating NIK stability, impacting cell fate decisions.