Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain

Cell Signal. 2007 Oct;19(10):2056-67. doi: 10.1016/j.cellsig.2007.05.016. Epub 2007 Jun 14.


RIP3 (Receptor Interacting Protein 3), a member of the Ser/Thr kinase family, is able to induce apoptosis and activate NF-kappaB in various cell types. However, the detailed mechanism of RIP3-induced apoptosis is largely unknown. In this study, we show that RIP3 is cleaved at Asp328 by caspase-8 under apoptotic stimuli, which is blocked by pan-caspase inhibitor Z-VAD-FMK. In addition, full-length RIP3 induces both caspase-dependent and-independent apoptosis, as well as activates NF-kappaB. However, after cleavage, the C-terminus of RIP3 (aa 329-518) that lacks the kinase domain can form punctuate or filaments-like structures in cytoplasm, which induces only caspase-dependent apoptosis and exhibits a markedly higher NF-kappaB-activating activity than full-length RIP3. More importantly, the cleaved product of RIP3 (aa 329-518) displays better stability than wild type RIP3. Additionally, RIP3(K50A), a kinase-dead RIP3 mutant, also induces only caspase-dependent apoptosis along with an increased NF-kappaB-activating activity compared to RIP3, which further demonstrates that kinase activity of RIP3 is essential for its caspase-independent apoptotic activity. These results will help us to understand the mechanism underlying RIP3-induced apoptosis and the different roles of kinase domain and unique domain of RIP3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 8 / metabolism
  • Caspases / metabolism*
  • Catalytic Domain
  • Cell Line
  • Humans
  • NF-kappa B / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction


  • NF-kappa B
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8
  • Caspases