Identification of RIP1 kinase as a specific cellular target of necrostatins
Identification of RIP1 kinase as a specific cellular target of necrostatins
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DOI：
10.1038/nchembio.83
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发表时间：
2008-05-01
影响因子：
14.8
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
坏死性凋亡是由凋亡刺激诱导的坏死细胞死亡的细胞机制，其形式为在凋亡执行被阻止的条件下通过其各自的配体的死亡结构域受体接合。虽然它发生在调节条件下，坏死性细胞死亡的特征是相同的形态学特征，作为非调节性坏死性死亡。在这里，我们报告，necrostatin-1，以前确定的坏死性凋亡的小分子抑制剂，是一种选择性的变构抑制剂的死亡结构域受体相关的衔接激酶RIP 1在体外。我们发现，RIP 1是necrostatin-1的抗凋亡活性的主要细胞靶点。此外，我们发现，其他两个necrostatin，necrostatin-3和necrostatin-5，也针对RIP 1激酶的步骤在坏死性凋亡途径，但通过不同的机制，从necrostatin-1。总体而言，我们的数据确立了necrostatin作为RIP 1激酶的第一类抑制剂，RIP 1激酶是参与坏死性凋亡激活的关键上游激酶。
Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.