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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
Summary
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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