Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain
Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain
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RIP3 的裂解通过去除激酶结构域使其不依赖 caspase 的细胞凋亡途径失活
DOI：
10.1016/j.cellsig.2007.05.016
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发表时间：
2007-10-01
影响因子：
4.8
通讯作者：
Wu, Mian
中科院分区：
文献类型：
--
作者：
Feng, Shanshan;Yang, Yonghui;Wu, Mian
RIP 3（Receptor Interacting Protein 3，受体相互作用蛋白3）是Ser/Thr激酶家族的一员，能够在多种细胞类型中诱导凋亡并激活NF-κ B B。然而，RIP 3诱导细胞凋亡的详细机制在很大程度上是未知的。在这项研究中，我们表明，RIP 3被切割在Asp 328的caspase-8的凋亡刺激下，这是由泛caspase抑制剂Z-VAD-FMK阻断。此外，全长RIP 3诱导半胱天冬酶依赖性和非依赖性细胞凋亡，以及激活NF-κ B。然而，切割后，缺乏激酶结构域的RIP 3的C-末端（aa 329-518）可以在细胞质中形成点状或类似于细胞质的结构，其仅诱导半胱天冬酶依赖性凋亡，并且表现出比全长RIP 3显著更高的NF-κ B活化活性。更重要的是，RIP 3的裂解产物（aa 329-518）显示出比野生型RIP 3更好的稳定性。此外，RIP 3（K50 A），一种激酶死亡的RIP 3突变体，也仅诱导半胱天冬酶依赖性细胞凋亡，与RIP 3相比沿着增加的NF-κ B激活活性，这进一步证明RIP 3的激酶活性对其半胱天冬酶非依赖性细胞凋亡活性是必需的。这些结果将帮助我们了解RIP 3诱导细胞凋亡的机制以及RIP 3的激酶结构域和独特结构域的不同作用，（c）2007 Elsevier Inc. All rights reserved.
RIP3 (Receptor Interacting Protein 3), a member of the Ser/Thr kinase family, is able to induce apoptosis and activate NF-kappa B 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-kappa B. 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-kappa B-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-kappa B-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, (c) 2007 Elsevier Inc. All rights reserved.