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Cell Signal. 2007 Oct;19(10):2056-67. Epub 2007 Jun 14.

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

Author information

1
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.

Abstract

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.

PMID:
17644308
DOI:
10.1016/j.cellsig.2007.05.016
[Indexed for MEDLINE]

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