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Ripoptosome: a novel IAP-regulated cell death-signalling platform

Gergely Imre1, Sarit Larisch, Krishnaraj Rajalingam

  • 1Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.

Journal of Molecular Cell Biology
|November 25, 2011
PubMed

Insights

Programmed cell death, including necroptosis, is regulated by RIPK1. A newly identified Ripoptosome complex mediates apoptosis and necroptosis, but is inhibited by cIAPs and XIAP.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Cell death pathways, including apoptosis and necroptosis, are critical for organismal homeostasis.
  • The receptor-interacting serine-threonine kinase 1 (RIPK1) is a key regulator determining cell fate.
  • Understanding the molecular mechanisms governing the switch between cell death modalities is crucial.

Purpose of the Study:

  • To identify novel protein complexes involved in regulating programmed cell death.
  • To elucidate the role of RIPK1 in mediating both apoptosis and necroptosis.
  • To investigate the regulatory mechanisms controlling the newly discovered Ripoptosome complex.

Main Methods:

  • Biochemical assays to characterize protein complexes.
  • Analysis of cellular responses to genotoxic stress and Toll-like receptor 3 (TLR3) stimulation.
  • Investigating the role of specific kinases and ubiquitin ligases in cell death pathways.

Main Results:

  • A ~2 MDa cytosolic complex, termed the 'Ripoptosome', was identified, containing RIPK1.
  • The Ripoptosome mediates both apoptosis and necroptosis in response to specific stimuli.
  • Cellular inhibitors of apoptosis proteins (cIAPs) and X-linked inhibitor of apoptosis protein (XIAP) were found to inhibit the Ripoptosome via ubiquitination.

Conclusions:

  • The Ripoptosome is a novel signaling hub that integrates signals to control cell death.
  • RIPK1's kinase activity and its incorporation into the Ripoptosome are critical for its function.
  • Ubiquitination by cIAPs and XIAP provides a negative feedback mechanism to regulate Ripoptosome-mediated cell death.

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