RIPK1-mediated监管坏死

稳定的标识符
r - hsa - 5213460
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RIPK1-mediated监管坏死
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受体相互作用的丝氨酸/苏氨酸激酶蛋白1 (RIPK1)和ripk3依赖性坏死称为坏死或程序性坏死。RIPK1和RIPK3的激酶活性对人、小鼠细胞系和遗传小鼠模型的坏死细胞死亡至关重要(Cho YS et al. 2009;He S et al. 2009, 2011;张德伟等。2009;McQuade T et al. 2013;Newton et al. 2014)。坏死的开始可以由激活外部凋亡信号通路的死亡配体刺激,如肿瘤坏死因子(TNF) α、Fas配体(FasL)和TRAIL (TNF相关凋亡诱导配体)或toll样受体3和4配体(Holler N et al. 2000;He S et al. 2009;Feoktistova M et al. 2011;Voigt S et al. 2014)。 In contrast to apoptosis, necroptosis represents a form of cell death that is optimally induced when caspases are inhibited (Holler N et al. 2000; Hopkins-Donaldson S et al. 2000; Sawai H 2014). Specific inhibitors of caspase-independent necrosis, necrostatins, have recently been identified (Degterev A et al. 2005, 2008). Necrostatins have been shown to inhibit the kinase activity of RIPK1 (Degterev A et al. 2008). Importantly, cell death of apoptotic morphology can be shifted to a necrotic phenotype when caspase 8 activity is compromised, otherwise active caspase 8 blocks necroptosis by the proteolytic cleavage of RIPK1 and RIPK3 (Kalai M et al. 2002; Degterev A et al. 2008; Lin Y et al. 1999; Feng S et al. 2007). When caspase activity is inhibited under certain pathophysiological conditions or by pharmacological agents, deubiquitinated RIPK1 is engaged in physical and functional interactions with the cognate kinase RIPK3 leading to formation of necrosome, a necroptosis-inducing complex consisting of RIPK1 and RIPK3 (Sawai H 2013; Moquin DM et al. 2013; Kalai M et al. 2002; Cho YS et al. 2009, He S et al. 2009, Zhang DW et al. 2009). Within the necrosome RIPK1 and RIPK3 bind to each other through their RIP homotypic interaction motif (RHIM) domains. The RHIMs can facilitate RIPK1:RIPK3 oligomerization, allowing them to form amyloid-like fibrillar structures (Li J et al. 2012; Mompean M et al. 2018). RIPK3 in turn interacts with mixed lineage kinase domain-like protein (MLKL) (Sun L et al. 2012; Zhao J et al. 2012; Murphy JM et al. 2013; Chen W et al. 2013). The precise mechanism of MLKL activation by RIPK3 is incompletely understood and may vary across species (Davies KA et al. 2020). Mouse MLKL activation relies on transient engagement of RIPK3 to facilitate phosphorylation of the pseudokinase domain (Murphy JM et al. 2013; Petrie EJ et al. 2019a), while it appears that stable recruitment of human MLKL by necrosomal RIPK3 is an additional crucial step in human MLKL activation (Davies KA et al. 2018; Petrie EJ et al. 2018, 2019b). RIPK3-mediated phosphorylation is thought to initiate MLKL oligomerization, membrane translocation and membrane disruption (Sun L et al. 2012; Wang H et al. 2014; Petrie EJ et al. 2020; Samson AL et al. 2020). Studies in human cell lines suggest that upon induction of necroptosis MLKL shifts to the plasma membrane and membranous organelles such as mitochondria, lysosome, endosome and ER (Wang H et al. 2014), but it is trafficking via a Golgi-microtubule-actin-dependent mechanism that facilitates plasma membrane translocation, where membrane disruption causes death (Samson AL et al. 2020). The mechanisms of necroptosis regulation and execution downstream of MLKL remain elusive. The precise oligomeric form of MLKL that mediates plasma membrane disruption has been highly debated (Cai Z et al. 2014; Chen X et al. 2014; Dondelinger Y et al. 2014; Wang H et al. 2014; Petrie EJ et al. 2017, 2018; Samson AL et al. 2020 ). However, microscopy data revealed that MLKL assembles into higher molecular weight species upon cytoplasmic necrosomes within human cells, and upon phosphorylation by RIPK3, MLKL is trafficked to the plasma membrane (Samson AL et al. 2020). At the plasma membrane, phospho-MLKL forms heterogeneous higher order assemblies, which are thought to permeabilize cells, leading to release of DAMPs to invoke inflammatory responses. While RIPK1, RIPK3 and MLKL are the core signaling components in the necroptosis pathway, many additional molecules have been proposed to positively and negatively tune the signaling pathway. Currently, this picture is evolving rapidly as new modulators continue to be discovered.

Reactome模块描述了质膜上mlkl介导的坏死事件。

文献引用
PubMed ID 标题 杂志 一年
31712266 杀手伪激酶混合谱系激酶结构域样蛋白(MLKL)

墨菲,JM

冷泉Harb展望Biol 2020
24452471 调控性坏死:非凋亡细胞死亡通路网络的扩张

Vanden Berghe TLinkermann,Jouan-Lanhouet,年代查克,H凡,P

Nat, Rev. Mol,《细胞生物学》。 2014
24773756 tnf诱导的caspase非依赖性坏死的特征

Sawai, H

Leuk。Res。 2014
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