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Intermediate domain of receptor-interacting protein kinase 1 (RIPK1) determines switch between necroptosis and RIPK1

Linde Duprez1, Mathieu J M Bertrand, Tom Vanden Berghe

  • 1Department for Molecular Biomedical Research-VIB, Ghent University, Technologiepark 927, Gent-Zwijnaarde 9052, Belgium.

The Journal of Biological Chemistry
|February 25, 2012
PubMed

Insights

Receptor-interacting protein kinase 1 (RIPK1) has an anti-apoptotic role in its intermediate domain. This study presents a novel RIPK1 kinase-dependent apoptosis model.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Receptor-interacting protein kinase 1 (RIPK1) is a key regulator in the tumor necrosis factor receptor 1 (TNFR1) pathway.
  • RIPK1 mediates diverse cellular outcomes, including MAPK/NF-κB activation and cell death (apoptosis and necroptosis).

Purpose of the Study:

  • To investigate the role of the RIPK1 intermediate domain (ID) in TNFR1 signaling.
  • To establish a genetic model for studying RIPK1 kinase-dependent apoptosis.

Main Methods:

  • Utilized a mutant RIPK1 (RIPK1ΔID) lacking the intermediate domain.
  • Analyzed RIPK1 and caspase-8 recruitment to Fas-associated death domain (FADD) within the TNFR1 complex II.
  • Employed the RIPK1 kinase inhibitor necrostatin-1.

Main Results:

  • The RIPK1 intermediate domain is crucial for TNFR1-mediated signaling events.
  • RIPK1ΔID expression shifted TNF-induced cell death from necroptosis to apoptosis in L929 cells.
  • Necrostatin-1 inhibited RIPK1 and caspase-8 recruitment, blocking apoptosis, highlighting RIPK1 kinase activity's role.

Conclusions:

  • RIPK1 possesses an anti-apoptotic function mediated by its intermediate domain.
  • A novel cellular system was developed for studying RIPK1 kinase-dependent apoptosis, independent of cIAP1/2 depletion.

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