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正向和负向磷酸化调节RIP1和RIP3诱导的程序性坏死。

Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis.

作者信息

McQuade Thomas, Cho Youngsik, Chan Francis Ka-Ming

机构信息

*Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, U.S.A.

出版信息

Biochem J. 2013 Dec 15;456(3):409-15. doi: 10.1042/BJ20130860.

Abstract

Programmed necrosis or necroptosis is controlled by the action of two serine/threonine kinases, RIP1 (receptor-interacting serine/threonine protein kinase 1; also known as RIPK1) and RIP3. The phosphorylation of RIP1 and RIP3 is critical for assembly of the necrosome, an amyloid-like complex that initiates transmission of the pro-necrotic signal. In the present study, we used site-directed mutagenesis to systematically examine the effects of putative phosphoacceptor sites on RIP1 and RIP3 on TNF (tumour necrosis factor)-induced programmed necrosis. We found that mutation of individual serine residues in the kinase domain of RIP1 had little effect on RIP1 kinase activity and TNF-induced programmed necrosis. Surprisingly, an alanine residue substitution for Ser(89) enhanced RIP1 kinase activity and TNF-induced programmed necrosis without affecting RIP1-RIP3 necrosome formation. This indicates that Ser(89) is an inhibitory phosphoacceptor site that can dampen the pro-necrotic function of RIP1. In addition, we show that a phosphomimetic mutant of RIP3, S204D, led to programmed necrosis that was refractory to RIP1 siRNA and insensitive to necrostatin-1 inhibition. Our results show that programmed necrosis is regulated by positive and inhibitory phosphorylation events.

摘要

程序性坏死或坏死性凋亡由两种丝氨酸/苏氨酸激酶RIP1(受体相互作用丝氨酸/苏氨酸蛋白激酶1;也称为RIPK1)和RIP3的作用所控制。RIP1和RIP3的磷酸化对于坏死小体的组装至关重要,坏死小体是一种淀粉样复合物,可启动促坏死信号的传递。在本研究中,我们使用定点诱变系统地研究了RIP1和RIP3上假定的磷酸化位点对肿瘤坏死因子(TNF)诱导的程序性坏死的影响。我们发现,RIP1激酶结构域中单个丝氨酸残基的突变对RIP1激酶活性和TNF诱导的程序性坏死影响很小。令人惊讶的是,用丙氨酸残基取代Ser(89)可增强RIP1激酶活性和TNF诱导的程序性坏死,而不影响RIP1-RIP3坏死小体的形成。这表明Ser(89)是一个抑制性磷酸化位点,可抑制RIP1的促坏死功能。此外,我们表明RIP3的模拟磷酸化突变体S204D导致程序性坏死,该坏死对RIP1 siRNA具有抗性且对坏死抑制剂-1抑制不敏感。我们的结果表明,程序性坏死受正向和抑制性磷酸化事件的调节。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45cc/4143978/508f54464dce/nihms617673f1.jpg

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RIP3: a molecular switch for necrosis and inflammation.RIP3:坏死和炎症的分子开关。
Genes Dev. 2013 Aug 1;27(15):1640-9. doi: 10.1101/gad.223321.113.
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Structural basis of RIP1 inhibition by necrostatins.坏死菌素抑制 RIP1 的结构基础。
Structure. 2013 Mar 5;21(3):493-9. doi: 10.1016/j.str.2013.01.016.

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