StIKKing it to a death kinase: IKKs prevent TNF-α-induced cell death by phosphorylating RIPK1
StIKKing it to a death kinase: IKKs prevent TNF-α-induced cell death by phosphorylating RIPK1
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DOI：
10.1016/j.cyto.2015.10.014
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发表时间：
2016-02-01
期刊：
影响因子：
3.8
通讯作者：
Balachandran, Siddharth
中科院分区：
文献类型：
--
作者：
Dillon, Christopher P.;Balachandran, Siddharth
由细胞因子TNF-α激活的信号传导途径是所有哺乳动物生物学中研究最深入和理解最透彻的。在一个简单的模型中，两个主要信号来自TNF-α受体，一个通过NF-κ B转录反应激活细胞存活，另一个在细胞存活信号被中和时触发细胞死亡。激酶RIPK 1参与了这两个轴，它的多聚泛素化被认为是它在生存与死亡信号之间切换的主要机制。当RIPK 1被泛素化时，它在IKK募集和随后的NF-κ B活化中作为非酶促衔接蛋白发挥作用;当RIPK 1的泛素化被阻止时，它作为能够触发细胞凋亡或坏死性凋亡的细胞死亡激酶发挥作用。Bertrand及其同事（Dondelinger等人，2015）现在证明RIPK 1的磷酸化代表了这种蛋白质在其生命和死亡职责之间切换的另一种机制。他们表明IKK-α和IKK-β都磷酸化RIPK 1，抑制其将死亡效应因子FADD和caspase 8组装成功能性促凋亡信号体的能力。这些IKK还保护免受RIPK 1介导的坏死性凋亡。重要的是，IKK-α/β独立于NF-κ B转录应答阻止RIPK 1驱动的细胞死亡。这些发现将IKK对RIPK 1的磷酸化确定为一种新的机制。调节TNFR 1下游的细胞命运决定。(C)2015爱思唯尔有限公司版权所有。
Signaling pathways activated by the cytokine TNF-alpha are among the most intensively studied and well-understood in all mammalian biology. In a simplistic model, two primary signals emanate from the TNF-alpha receptor, one that activates cell survival via an NF-kappa B transcriptional response and a second that triggers cell death when cell survival signals are neutralized. The kinase RIPK1 participates in both these axes, and its poly-ubiquitylation was thought to represent the primary mechanism by which it toggles between survival versus death signaling. When RIPK1 is ubiquitylated, it acts non-enzymatically as an adaptor protein in IKK recruitment and subsequent NF-kappa B activation; when ubiquitylation of RIPK1 is prevented, it functions as a cell death kinase capable of triggering apoptosis or necroptosis. Bertrand and colleagues (Dondelinger et al., 2015) now demonstrate that phosphorylation of RIPK1 represents an additional mechanism by which this protein switches between its life and death duties. They show that both IKK-alpha and IKK-beta phosphorylate RIPK1, dampening its capacity to assemble the death effectors FADD and caspase 8 into a functional pro-apoptotic signalsome. These IKKs also protect against RIPK1-mediated necroptosis. Importantly, IKK-alpha/beta prevent RIPK1-driven cell death independently of NF-kappa B transcriptional responses. These findings identify phosphorylation of RIPK1 by IKKs as a new mechanism by which. cell fate decisions downstream of TNFR1 are regulated. (C) 2015 Elsevier Ltd. All rights reserved.