RIPK1-and RIPK3-induced cell death mode is determined by target availability
RIPK1-and RIPK3-induced cell death mode is determined by target availability
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DOI：
10.1038/cdd.2014.70
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发表时间：
2014-10-01
影响因子：
12.4
通讯作者：
Vaux, D. L.
中科院分区：
文献类型：
--
作者：
Cook, W. D.;Moujalled, D. M.;Vaux, D. L.
受体相互作用蛋白激酶1 （RIPK1）和RIPK3都可以在死亡受体连接后发出细胞死亡信号。为了研究在缺乏死亡受体信号的情况下ripk触发细胞死亡的要求，我们设计了RIPK1和RIPK3的诱导版本，它们可以通过抗生素库默霉素的二聚体激活。在缺乏TNF或其他死亡配体的情况下，RIPK1的表达和二聚化足以通过caspase或ripk3依赖机制导致细胞死亡。二聚体RIPK3通过mlkl依赖的机制诱导细胞死亡，但令人惊讶的是，它也诱导FADD、caspase 8和RIPK1介导的死亡。催化活性的RIPK3激酶结构域对于mlkl依赖性死亡是必需的，但对于caspase 8依赖性死亡则不是必需的。当RIPK1或RIPK3蛋白二聚化时，细胞死亡模式由下游分子如FADD、caspase 8和MLKL的可用性决定。这些观察结果表明，最终的机制取决于各自的信号和效应蛋白的水平，而不是在两种细胞死亡模式之间进行“切换”。
Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins.