Department for Molecular Biomedical Research, VIB, Zwijnaarde-Ghent, Belgium.
Cell Death Differ. 2012 Jan;19(1):75-86. doi: 10.1038/cdd.2011.164. Epub 2011 Nov 11.
The lab of Jürg Tschopp was the first to report on the crucial role of receptor-interacting protein kinase 1 (RIPK1) in caspase-independent cell death. Because of this pioneer finding, regulated necrosis and in particular RIPK1/RIPK3 kinase-mediated necrosis, referred to as necroptosis, has become an intensively studied form of regulated cell death. Although necrosis was identified initially as a backup cell death program when apoptosis is blocked, it is now recognized as a cellular defense mechanism against viral infections and as being critically involved in ischemia-reperfusion damage. The observation that RIPK3 ablation rescues embryonic lethality in mice deficient in caspase-8 or Fas-associated-protein-via-a-death-domain demonstrates the crucial role of this apoptotic platform in the negative control of necroptosis during development. Here, we review and discuss commonalities and differences of the increasing list of inducers of regulated necrosis ranging from cytokines, pathogen-associated molecular patterns, to several forms of physicochemical cellular stress. Since the discovery of the crucial role of RIPK1 and RIPK3 in necroptosis, these kinases have become potential therapeutic targets. The availability of new pharmacological inhibitors and transgenic models will allow us to further document the important role of this form of cell death in degenerative, inflammatory and infectious diseases.
朱尔格·屈普（Jürg Tschopp）实验室首次报道了受体相互作用蛋白激酶 1（RIPK1）在半胱天冬酶非依赖性细胞死亡中的关键作用。由于这一开创性发现，调控性坏死，特别是 RIPK1/RIPK3 激酶介导的坏死，被称为坏死性凋亡，已成为一种备受关注的调控性细胞死亡形式。尽管最初坏死被鉴定为细胞凋亡被阻断时的备用细胞死亡程序，但现在它被认为是一种针对病毒感染的细胞防御机制，并被认为在缺血再灌注损伤中起着至关重要的作用。RIPK3 缺失可挽救缺乏半胱天冬酶-8 或 Fas 相关死亡域蛋白的小鼠的胚胎致死性，这一观察结果证明了该凋亡平台在发育过程中对坏死性凋亡的负调控中的关键作用。在这里，我们回顾和讨论了从细胞因子、病原体相关分子模式到多种形式的物理化学细胞应激等不断增加的调控性坏死诱导剂的共性和差异。自 RIPK1 和 RIPK3 在坏死性凋亡中的关键作用被发现以来，这些激酶已成为潜在的治疗靶点。新的药理学抑制剂和转基因模型的出现将使我们能够进一步证明这种细胞死亡形式在退行性、炎症和传染性疾病中的重要作用。
