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TNF can activate RIPK3 and cause programmed necrosis in the absence of RIPK1

D M Moujalled1, W D Cook, T Okamoto

  • 1The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria, Australia.

Cell Death & Disease
|January 19, 2013
PubMed

Insights

Tumor necrosis factor receptor 1 (TNFR1) signaling can induce cell death. This study shows receptor-interacting protein kinase 1 (RIPK1) is not essential for TNFR1-induced RIPK3 activation and cell death.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Immunology

Background:

  • Tumor necrosis factor receptor 1 (TNFR1) signaling triggers cell death via caspase-8 or RIPK1/RIPK3 pathways.
  • RIPK1's death domain was thought essential for RIPK3 recruitment into death complexes.

Purpose of the Study:

  • To investigate if RIPK1 is essential for RIPK3 activation and subsequent cell death upon TNFR1 ligation.
  • To determine the role of RIPK1 in TNF-induced necroptosis and ripoptosome/necrosome formation.

Main Methods:

  • Overexpression of RIPK3 in wild-type and gene-deleted murine embryonic fibroblasts (MEFs).
  • Stimulation with TNF in the presence of caspase inhibitors.
  • Analysis of cell death in response to TNF and RIPK3 levels.

Main Results:

  • Elevated RIPK3 levels enabled TNF to induce cell death in WT, Ripk1(-/-), caspase 8(-/-), and Bax(-/-)/Bak(-/-) MEFs.
  • Cell death occurred independently of RIPK1, involving both caspase-8-dependent and caspase/Bax/Bak-independent pathways.
  • TNFR1 and TRADD were essential for TNF-induced cell death, confirming receptor-dependent signaling.

Conclusions:

  • RIPK1 is not essential for TNF-induced RIPK3 activation or cell death.
  • RIPK3 can be activated by TNF independently of RIPK1, leading to necroptosis.
  • This challenges the necessity of RIPK1 for ripoptosome/necrosome complex formation and function.

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