坏死性下垂
程序性细胞死亡
细胞生物学
激酶
裂谷1
生物
信号转导
细胞凋亡
蛋白激酶A
化学
生物化学
作者
Alexei Degterev,Junichi Hitomi,Megan Germscheid,Irene L. Ch’en,Olga Korkina,Xin Teng,Derek W. Abbott,Gregory D. Cuny,Chengye Yuan,Gerhard Wagner,Stephen M. Hedrick,Scott A. Gerber,Alexey A. Lugovskoy,Junying Yuan
摘要
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.
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