Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Sci Signal. 2021 Feb 2;14(668):eabc6178. doi: 10.1126/scisignal.abc6178.
Necroptosis is a lytic, proinflammatory cell death pathway, which has been implicated in host defense and, when dysregulated, the pathology of many human diseases. The central mediators of this pathway are the receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3 and the terminal executioner, the pseudokinase mixed lineage kinase domain-like (MLKL). Here, we review the chronology of signaling along the RIPK1-RIPK3-MLKL axis and highlight how the subcellular compartmentalization of signaling events controls the initiation and execution of necroptosis. We propose that a network of modulators surrounds the necroptotic signaling core and that this network, rather than acting universally, tunes necroptosis in a context-, cell type-, and species-dependent manner. Such a high degree of mechanistic flexibility is likely an important property that helps necroptosis operate as a robust, emergency form of cell death.
细胞坏死是一种溶酶体依赖性的、伴有炎症反应的细胞程序性死亡方式，其在宿主防御中发挥重要作用，而当其失调时则会引起多种人类疾病的发生。该途径的核心介质是受体相互作用丝氨酸/苏氨酸蛋白激酶 RIPK1 和 RIPK3 以及末端执行器，即假激酶混合谱系激酶结构域样（MLKL）。在这里，我们回顾了 RIPK1-RIPK3-MLKL 轴上的信号传递顺序，并强调了信号事件的亚细胞区室化如何控制细胞坏死的起始和执行。我们提出，一个包含多种调节剂的网络围绕着细胞坏死的信号核心，并且该网络不是普遍作用，而是以依赖于上下文、细胞类型和物种的方式来调节细胞坏死。这种高度的机制灵活性可能是细胞坏死作为一种强大的、紧急形式的细胞死亡的重要特性。
